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Remdesivir – potential drug for COVID-19 shows promise

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– Good afternoon, everyone. I’m Lindsey Criswell, the
vice chancellor of Research. I’d to welcome you to
the third of a seriesof COVID-19-related research town halls,sponsored by the Office of Research. Today’s event will focus
on COVID-19 researchunderway within Quantitative
Biosciences Institute,or QBI, at UCSF,and as with the previous
Office of Research town halls,a recording of this event,along with the answers to
the questions submitted,will be available at the
Office of Research website. Please also note that another town hallis planned for tomorrow at four o’clock. That will be our third
in a series of eventsco-hosted with the Academic
Senate that focus onresearch operations during
the COVID-19 pandemic. I hope you will all be joining us tomorrowfor that town hall. And now I’m going to turn
things over to David Morgan,our vice dean for Research
for the School of Medicine,who will moderate today’s town hall. Thanks, David. – Okay. Hello everyone and welcome. We have a very special
event for you today. We’re gonna hear about
a lot of really excitingnew discoveries in the science
of COVID-2 and COVID-19from the Quantitative
Biosciences Institute. I think many of you know
that a lot of labs at UCSFhave pivoted recently
to COVID-19 research,especially since the shutdown occurredin the last couple of months. But I don’t think any lab,
not quite as early as startas the lab of Nevan Krogan,who started working on this problemprobably in a roundabout late January. And so they’ve been working on the virus,the infection process
and potential treatmentsfor about three or four months now. And so we’re gonna hear
about a lot of their excitingrecent developments in that area. So, as the first slide showed,we’re going to hold all questionsuntil the end of all the talks. We have five talks, as you can see here. We’re gonna keep our eye on
the question and answer boxin the Zoom video. And then at the end,I will get together with Kevan Shokat,we’ll moderate the
question period at the end. So, without further ado,
here is Nevan Krogan,director of the Quantitative
Biosciences Instituteto start the show, Nevan. – Great. Thank you, Dave and Lindsay
for coordinating this. We are delighted to be telling
you about some of the ongoingresearch at the Quantitative
Biosciences Institute,which is in the school
of pharmacy here at UCSF. In particular the efforts of the QCRG,the QBI Coronavirus or
COVID-19 Research Group. And as Dave said, this is a
group that has come togethera couple of months ago. Initially it was 22 laboratories
and since its inceptionat the end of February,
it’s actually expanded nowto over 41 groups at UCSF,encompassing essentially
hundreds of different scientists. And the group has gotten so large,we’ve actually had to now split
it into different subgroups. There’s now 10 different
subgroups associated with QCRGfocused on different technologiesor approaches as well as
different biological areas. And you’re gonna hear talks
from four different subgroups. The first hear from Davide Ruggero,it’s focused on translation. And then Brian Schoichet
who along with Kevan Schokatruns the drug discovery subgroup. And then Kliment Verba
is gonna give an updateon the structural biology work. He runs this subgroup with Oren Rosenberg. And then Shaeri Mukherjee
at the end will talk aboutthe efforts with respect
to approaching trafficking. And if anyone’s interested in joiningany of these subgroups,please reach out to
these different leaders. And if you’d like to
form your own subgroups,please reach out to us. There’s actually a couple of new subgroupsthat are gonna be forming
in the near future. And at QBI we’re really
about collaborationover the last three, four years. And in this example, it’s no different. The work you’re gonna hear
about today was done jointlyat QBI UCSF with Mount Sinaiand the Institut Pasteur in
Paris that it involves a numberof other groups really around the world. And for me it has been a
great honor and pleasureto be involved in this
really collaborative effortthat’s going on over
the last three months. And I’m looking forward
for more collaborationsultimately in the future. And I think as Dave alluded
to this is one of the projectsthat came out of the QCRG. It was published a few days ago,and this is what I’m gonna
be briefly talking about. It’s the A SARS CoV-2 to
protein interaction mapthat we generated and how
we used it to identify drugsand compounds that we’re
trying to repurpose to seeif they’re useful in terms
of fighting off COVID-19. There’s over 120 authors on
this paper and over 35 groupsI think represented from around the world. And I know a lot of people
are focusing their attentionon trying to get drugs
or compounds to targetthe viral proteins themselves,
which is a great strategy. In this paper we took a
little different approach,and ultimately we’re
trying to target the host,target the human proteins
that the virus needsin order to infect ourselves. And there’s advantages to that. You don’t have to worry
so much about resistance’cause we don’t mutate as
fast as the different viruses. And ultimately as we and others have shownis that it’s similar
human genes and proteinsthat are being hijacked
by different viruses. Not even in the same
family as these viruses. So, ultimately the vision would
be if we’ve got a strategy,a whole structured strategy for COVID-19,it would work for COVID-22, COVID-24,and even other viruses. There’s obviously a disadvantage here. You have to worry about toxicity,But we initially focused our
attention on FDA approved drugsand compounds that are in clinical trialsthat are past the toxicity stage,so that the logic would be
that we wouldn’t have to worryso much about toxicity. So, there’s a close to 30 genes associatedwith the SARS CoV-2 virus comparedto over 20,000 in our cells. And so the virus itself obviouslycan’t live without our cells. It needs our cells, our genes,
our proteins in order to liveand replicate and infect our our bodies. And the vision here is, well,
let’s find all the humanproteins that the virus
needs in order to infect us. So, we carried on a
project where we identifiedover 300 proteins, which we
think are enriched four proteinsthat the virus does need. And then we use this set to identify69 different drugs and compounds. And just a little bit more
detail on the experiment itself. We used mass spectrometry after
affinity take purificationaspect to generate this map,which you gonna hear a
little bit about today. And this map is now fueling
more hypothesis driven researchin the world that biochemistry,
structural biology,chemical biology and bioinformatics. And one of our goals
is to try to integrateall this information together
to find the key nodesor pathways or proteins in
our cells that the virus needsso that we can pharmacologically
or genetically inhibit themand then carry out infection experiments. And then this data in a reader
of weight would then helpre-inform this experimental
and computational pipeline. So, here’s a list of
the genes that we thinkare associated with the virus. There’s some debate about
some of these genes. We tried to be all in a
comprehensive, at least initially. So there’s 16 different
nonstructural proteins,four structural proteinsand then a number of very
interesting accessory proteins. And what we did, and this is
what we’ve done in the pastwith many other viruses,
put affinity tags on them,express them at least initially
here in HEK293T cells,purify these proteins,analyze the material by mass spectrometry,and then use algorithms that
we’ve developed to come upwith a high confidence SARS-CoV-2human protein protein interaction map. And I think the QCRG was
the first group in the worldthat actually had cloned
out each one of these genes. And when we initially
released our paper in bioRxiv,we tweeted out to the world and we said,”All right, whoever wants these plasmids,”we’ll send them to you for free. “No MTAs, please feel free to distribute. “And Dave Gordon and his crew with few CRGsent out to 318 different
labs in 38 countries,this set of a plasmid. I think that the plasmid
went around the worlda lot faster than the virus did. So, we’re really excited that
we’re able to help expediteSARS-2 research around the
world in this particular way. So, here’s the map that was generatedand published a few days ago. So it’s 332 SARS-CoV-2 human
protein protein interactions,including 69 different
druggable host factors. The diamonds here are the SARS-2 proteins. The circles here are the human proteins. If it’s an orange, we
think it’s a drug target. And I’d like to say we
collaborated with the ZOIC Labswho generated a very interactive
way to peruse this data. So, I think it’s really
cool how you can lookat this information in a
number of different ways. So, I’d encourage you
to look at this websitethat’s affiliated with the
paper if you’re interestedin looking deeper at
some of this information. So, then this map was looked
at by some really greatchemical biologists at UCSF Kevan Shokatand Brian Schoichet and and others. And they identified 69
different drugs and compounds. And ultimately with collaborators,we tested about two thirds of
these in virological assaysin a couple of different
places in the world. At the time unfortunately,we didn’t have the virus
propagating in UCSF. There’s been some great work being doneby a number of people now includingMelanie Ott Gladstone lab who
now has the virus propagating,and we’re starting to work with her. But there’s been two
collaborators that we’ve beenworking with over the last
few months to test these drugsand compounds including the
Institute pasture in Parisin particular, Marco Vignuzzi. He was born in Italy,
but raised in Canada. Therefore he’s a really
great collaborator. And then also Olivia Schwartz
and Christophe D’Enfert. This has been a relationship
that QBI had startedwith the Pasteur Institut
several years ago,and it really bore fruit here
in this particular pandemic. And then we’re also
collaborating very closelywith a good friend of mine
and Adolfo Garcia-Sastrereally one of the best
colleges in the world at theDepartment of Microbiology
at Mount Sinai in New York. And we’ve actually got a
lot of support to carry outthis research from a number
of different entities. We’ve actually been working
with the French consulatehere in San Francisco. QBI is having a couple events with them. And in order to make sure
that these drugs and compoundsgot to the Pasteur Institut in Paris,the French embassy actually got involvedto make sure that FedExwas sending these compounds to Paris. And then we have Todd here. This guy’s one of the heroes
of the story from FedEx. He was coming in and shipping
out these drugs and compoundsto New York and Paris and
shipping out all these plasmids. Actually we have his name
in the acknowledgementsof the paper, that’s well deserved. And then we were able to send
these drugs and compoundsto Pasteur and they
were able to test them. And just very briefly, just
to go through the assays,you’re gonna hear about
some of the results fromBrian and Davide. So, we’re using Vero6 cells. These are African green monkey cells. There’s now some better
human cells that can be used,but initially at the time
they weren’t available. So we initially used vero6 cells,and we’re growing up the cells,were adding drugs two
hours before we infect. There’s two different MOIs. One, the York MOIs is a little bit lowerthan what we see in Paris. The experiments it goes on
now for a couple of days. We kill everything with formaldehyde. And then in New York, what
they’re doing is using anantibody against NP is the
readout in a microscopy set up,And then looking at viral
titers with the TCID 50 assay. In Paris, they’re not
looking at the protein,they’re looking at the RNAand they have an RT-PCR experiment. And they’re combining that
also with a plaque assay. So, it’s similar assays, but different. And it was very reassuring
that we were seeing the sameresults in two different labs ultimatelyin two different continents. And in total, this is what
they initially screened for,is about 40 each and the total. If you look at collectively
47 of the drugs and compoundswere tested in total. And the first vignette
you’re gonna hear aboutis from David Ruggero, the
connection to translation. And just to show you here on this map,we found a number of connections
with some very interestingfactors linked to mRNA
translation regulation. and Davide is gonna to take it over nowand talk about some of that work. – Okay, great. Thank you, Nevan. So, I wanna start
actually with this slide. As many of you know, many
virus, including the CoV-2 viruswhen entering the cells
seek massive productionof viral proteins. Actually they just form
the cells in a factoryfor viral production. This is achieved through
hijacking a specific componentof the translation of
machinery in order to translatetheir own vital and mRNA at the expenseof the actually host and mRNA. And I actually didn’t make these slides,and I put the stock, but
often the use of this slideeven if I’m not a biologist. More to illustrate
actually a similar paradigmthat occurred in cancer. Whether we realize that
a key Oncogenic liaisons,also in cancer cell hijacked
like a specific componentof the translational machinery
to change the translationor efficiency of the specific
mRNAs that very importantfor tumor progression
or tumor translation. And actually we call now this Onco-mRNAs. And I’m gonna talk to the,It’s actually the two words met one day,but actually as you can
see this selection now,there’s an important lesson
to learn because what we areactually acceptably learning
in the cancer contextthis can be applicable for, of course,for the pandemic that to
be out of facing right now. And indeed the based on
the beautiful and the virusExosome interacting
characterized in the Kroghan lab,you can see that the key
vital proteins, in red,again interacted with
many factor that belongedto the transmission machinery,including the factoring
part of ribosome biogenesisor the factor that are importantto initiate the translation. These are known as the
translation incision factor. And I wanna highlight that
the never know the dimensionof specifically this factor
that’s called the elF4H. That is a factor that
stimulate like the activityof an helicase importantfor capita dependent translation. So, perhaps the reason why
indeed like the CoV-2 virushijack mainly translation
factor because again,as I said that like lie
when entering the cells,this is an a plus friend of the virus,the first thing has to do is massivelytranslate their own mRNA. And all the mRNA of the virus are capped. So they have like, this
is like the cap of mRNA,and the translation of this mRNAaccording to the capping
in the translation. But what’s intriguing is
actually the structureof the that
is here of this virus. As you can see, this is the. . . sorry, this is like a is
a structure that has beenbasically characterized in
the dust lab of Stanford. As you can see that it’s
like a lot of RPN loops,and usually this RPN loops
act as a translational barrierbecause the ribosome cannot
scan before to reach the AUG. So, the virus must rely on
not in the helicaseto unwind this 5UTR. But the structure for UTR
don’t therefore derive soneefficiency to initiate a translationof the vitamin in mRNA. So, I already mentioned
elF4H that the proteinthat actually interacted with
the specific viral protein. But what I wanna highlight
here is that the factthat elF4H is part of this
complex known also for elF4Fand this is a key. But I think complex that include the elF4Athat is the RNA helicase. elF4E that is the major
cap-binding proteinas well as to this protein. and this complex is really
important to basicallyrecruit the ribosome on
the 5UTR of the same RNA. And then with the help of,
again, the helicase activityelF4E, so this 5UTR is melting down,and now the ribosome reach of
the UTR Scaffold translation. So, of course the idea
here is that perhaps elF4Acan be a point of vulnerability
for this CoV-2 virus,and indeed that for other
corona virus there’s beensome person in the literature
where the inhibitoryfor elF4A not necessarily very
strong has a good activity,I guess, like this
coronavirus so like tighteras well as also other compounds
that targets this elF4Fcomplex also they have
an antiviral effect. But this is our two compounds. This is our two clinical compounds. So, based on this data,
based on our own data,so, we of course societal
rational to collaboratewith the effect of therapeutics. That is the first biotech
dedicated to developfor the first clinical compounds to targettranslation control in cancer. And I want to highlight
like cannot specificallythese compounds known as zotafitin,this is the best in class,
the first clinical compoundsthat target like this elF4A RNA Helicase. And this is zotatifin is
already in phase one and twofor solid cancer for the patients,exactly for cancer patients. So, as my colleague already mentioned,we send it to Mount Sinai or Paris,we send Zotatifin as well
as the other compound drugthat target compensation of
translation such like this two. As well as we also basically Jack Taunton,also send this great compounds. This is is a new compound,
very interest compoundsthat’s been generated in the
Jack Taunton Lab, in UCSF,is not necessarily Ternatin4. This compound that doesn’t
target initiation targetin other factor is called the eEF1A. That is an elongation
factor that is importantfor the elongation of the
like of course the translationas well as is important
perhaps for the frame shiftthat the virus undergo in
order to change the frameand produce some different vital proteins. And also important to
highlight that there is anothercompound that the structure iscompletely different from Ternatin. This is like it’s a different compound,but targets also eEF1A,
in medicine is a compoundthat is in clinical trial for
multiple myeloma in Australiaas well as for COVID-19 patients in Spain. And I also wanna highlight
another important aspectof this research, and
often like people askthe question, “Oh, but
targeting translation,”this can be detrimental
for host normal cells. “And actually what we learned
throughout the years,that two master genetics that
often this translation factorsare not a skippy factor
that actually are in accessin the cells because you
can reduce for example,elF4E or you can use elF4A. This mice are completely normal. You can go even below to 50%and this mice are still completely normal,but actually more protected
to actually develop for tumor. So, they’re saying of course
this concept phase for usis to think about this
drug report personnelto target to COVID, of course, 2-viral. And this is perhaps the
most important slidewhere the like many compoundsthat Nevan have already mentioned. So, these are two compounds stood outso they’re not in four, again,the target the elongation
start and that targetedthe RNA elF4A helicase. And this is the two acid,
and Nevan already mentionedin New York and Paris. So check of course, acid
for viral productioneither for assessing their viral proteinor for the virus RNA genome. As you can see from like them
red the curve in both cases,in two independent labs show
that the nanomolar digitsthese two compounds is
a very potent antiviralof course effect. For few compounds, this in
New York that has been alsotesting including Zotatifin,
so it’s been also testedfor reducing the virus
titer that it was producedby infected like cells, as you can see,that also in this case zotatifinhas very potent antiviral effect. Like reducing like viral
titer almost like to zero. So, what I want to
actually a non molar digitsthat is even lower than this assay. And I wanna end off here,
but of course again,highlighted the fact that the zotatifinis already in a human,is already in clinical trial for cancer. So we are working harder
with the QBI also to bring itso that it can also be in the clinicfor the COVID-19 patients. And I also end up to show exactlythe QCGR translation subgroup encapsulatedin the beautiful ribosome. They’re great. This is a great group, but
the majority uses UCSF. A few of them and also
from the Burke Institutethat actually we had a meeting
routinely to understandhow CoV-2 translational
work and how we can target. And the thanks for your attention. – All right, thank
you Davide, fantastic. Next up is Brian Schoichet,
who is gonna be talking abouta couple of receptors
QCRG have been working on. Very exciting receptors
’cause they’re very druggable. So, Brian. – Okay. I hope you can see my screen. This is a figure you’ve seen
before, at least partly. So there’s both the chemistry team here,the PIs and our collaborators
who are more on the biology,and our structural biology. And of course none of those
people do any of the work. The work is really done by the fabulousstudents and postdocs in the labs. And I wish I could go through
their names more carefully. So, I think you’ve seen a
version of this slide as well. This is a subset of the targets. The 332 targets that
the proteomics reveals. And it focuses on those of the
targets that can be drugged. And one of the startling
things for me from this projectso far, well, one of them is
just how many human proteinsare subverted by the virus. And then the other thing
is how big a subset it isof those human proteins that
either have drugs availablefor them or have really good
preclinical molecules for them. And sometimes mechanism of
action drugs, or drugs that hitthose targets as their
primary mechanism of action. But sometimes there molecules
that hit the targetsas a side effect or an
unintended consequence. So overall we looked at 1600 FDA drugs. A much larger. . . There’s not that many FDA drugs. That’s something that’s sort
of surprising to people. There’s only about 1800. We looked at about 20,000
investigational new drugsmolecules that have been in people,but are not approved for use,and about 4,000 PROMOs,
so preclinical molecules. And ultimately 29 drugs, 12
molecules that are in the clinicand 28 preclinical molecules
were tested against 63 targets. Not all of them have been tested yet,but they’re being tested. So, Davide mentioned the activity,the really fabulous activity
of the protein biogenesisinhibitors like zotatifin and
that it was a target classthat had some precedents as he showed you. Last expected on on two counts
were molecules targetingthe sigma-1 and sigma-2 receptors. They were, I think unexpected to usfor several reasons. One is sigma-1 and sigma-2 have not beenwidely implicated in antiviral biology. Once we knew about them
when we went to lookthrough the literature,
there is actually precedent,especially for sigma-1 being involvedin a viral lifestyle. And the other thing is
though, these are receptors,they’re sort of dark
horses in pharmacology,and have been for 40 years. The functions of these receptorsis still murky, especially the sigma-2. Sigma-1 is now widely
thought to be involvedin cell stress response. But even there, the mechanisms
are still really beingteased apart, and what it
might do as a drug targetis still kind of murky. But the great thing
about both receptors isthey find a lot of cationic
hydrophobic molecules. And cationic hydrophobic
molecule means a lot of drugs. And so we’ve been able to
find molecules that bindto those targets fairly
tightly, and sure enough,are antiviral in the assays
run in New York and Parisby Adolfo and Marco that
Nevan took you through. And so these are a few
of them that were foundand published in the paper. The IC50s range from about 215
nanomolar to 20 micromolar. These are here on the right
are these viral titer assaysthat Davide also took you through. The top one is PB-28, which
is a preclinical moleculethat’s potent on actually
both sigma receptors. With it got an IC 50 of about. . . sorry, in IC 90 about a 280 nanomolar. And then the the bottom
one is hydroxy chloroquine,which sort of a notorious
molecule now for Coronavirus,and it’s substantially
worse in the TCID assays. This is I think my last,
no, almost my last slide. So, it’s interesting to
counterpoint these observationswith the activity of
Remdesivir in the same assay. This is being published on bioRxiv,and then was redone actually. So the numbers agreed pretty well. It’s definitely antiviral,
but it’s not super strong,and you can compare it
to some of the othersigma active ligans, the
best of which are bindingin the 250 nanomolar range. Sorry, now binding are
active against the targetsin the 250 nanomolar range. And then finally there’s dextromethorphan. Dextromethorphan is ubiquitous
in cough medications. It’s an antitussive. You basically can’t buy a cough
medication that doesn’t havedextromethorphan in it in the U. Sunless you’re getting one with coding. And dextromethorphan is unlike
many of these other moleculesis actually a sigma-1 agonist. It’s lots to activate
the sigma-1 receptor,and sure enough it
shows pro viral effects,and that the red line
is the viral activity. So you can see us actually the
PF use, the log PF are goingup without affecting the cell viability. So, that’s actually a little bit alarming,but maybe consistent with the mechanism. And and then maybe the last
thing to say on this topicis that there’s a really
broad range of moleculesthat we found in terms of
their primary mechanismsand targets that are
antiviral in these assays. And the thing that unifies
them is they all hitthe sigma receptor. So, I think I’m out of time,
so I won’t dwell on this. The other approach we’re
taking in collaborationwith a lot of people on this
call is looking for target,starting with the target and
looking for new novel ligand. So this is a docking approach. The downside of this is
that it takes a lot longer. The first campaign we
started was in early Februaryfor the major protease and collaborationwith Charlie Craig’s lab and that’s take,we’re just now getting the compounds in,so it takes about three
months from start to finish,but the advantage of this is can reallyget a novel chemical matter. So we’re looking forward to
testing those things too. So, I’ll stop here. – Okay, fantastic. Brian, thank you so much. So next up is Kliment Verba, QBI fellow. He, along with Oren
Rosenberg have been in chargeof the structural biology QCRG subgroup,and he’s gonna tell you about
some very exciting pipelinesthat they have been setting up,along with some very
exciting antibody studiesas well that are being
done in his subgroup. So go ahead, Klim. I think Klim, you’re on mute. – One second. Can everyone see my screen and hear me?- Yeah, go ahead. – Yeah. Right, so our group as part
of QCRG has been taskedreally with bringing the molecular detailsto this picture. So, this is a part of the PMS dataset. And the idea is that if
you want to really designa small molecule inhibitors or biologics,we really want to understand,how do the active sites of
the viral proteins look like?How do the proteins come
together so that we can seizethose interfaces and
potentially design therapeuticsto break them apart. With experts from a structural biologist,scientists from around the
world, we now have structuresfor some of the viral proteins
feature indicated here. But the key point is
that most of them by farhas not been visualized at all. And so we’re really ends the ones,many of them are membrane proteins,which are involved with
three modelings and membranesin the host cells and human cells. And we really have no idea
how those proteins look like,how they work. And furthermore, even
sort of a darker spaceor darker space for us is
how do this protein complexesbetween virus protein and host proteinslook like once they come together. And without, again,
seeing those interfaces,it’s very hard to come up with waysof breaking those interactions apart. And so Nevan tasked Oren Rosenberg,a professor here at UCSF
and me was trying to havea cohesive structural biology effortsreally bringing some
clarity to this picture. And early on during our discussionsit became clear is that the canonical wayof doing structural biology where each labgrab a one or two of his
targets and then go after themwas not really going to cut it,if you really want to go
after this in a major way. And so we thought, why not
set this up as a consortiumwhere we make a call to the
structural biology communityat UCSF and say, “Hey, if
you wanna be part of this,”if you wanna contribute, please come join”and then we’ll work together on this. “And we’ll just prioritize target”and we’ll be one big effort
rather than splitting it apart”between different many different labs. “And so the amazing thing
is when we made the calls,the community respondedand it has been with amazing enthusiasm. And so within days we had
over 60 volunteers, which are,graduate students, postdocs
scientistsfrom 18 labs at UCSF who came
forward and say, basically,”Hey, I wanna be part of this. “How can I help?”And so, and I wanna know
that without the buy in,not just from the community,
but advisor faculty at UCSF,this would not have been possible. So, I think there’s
something unique too hereis that we can really
come together like this. And just put some
pictures, faces the nameshere is a screenshot of our
Friday meeting from last week. And this is just some
people in the consortium. So, we formed this QCRG
structural biology consortium. Once we had this many people,
the question was how dowe organize really to
have an efficient wayof going forward. And first thing we did was we formedsort of leadership
community, faculty at UCSFwho are really experienced
and wise to really help usstrategize the best way of doing this. And what came out of that
at the end of it is breakingthe effort up into lab groups,
which are really broken up byfunctional groups, nodes to some extent. And this is very akin to what you would doin an industry setting. And so we have groups focused
on expressing proteinsin the mammalian of bacterial systems. Then we pass those proteins
to purification groupand then the other groups which
do crystallography and data processing. And the key point is all
this groups are interlocked. It’s not that one lab does
one saying it was the other. It’s really the knowledge
just flows togetherand we figure out the best
way to do it as a community. And the way we set this up is each grouphas a faculty mentor. One to see faculty mentors for each group. And the next is actually
team leads who are eithergraduate students or postdocs
who sort of have more controlof our everyday operations
of each of these groups. And the group size between 15 to 30 peopledepending on what they’re doing. And so now that we have the
set up, what is it that weactually want to accomplish?What are our goals?And so we really have
a three prong approach. The first part, depicted
here is really going afterthe viral proteins to predominantly,
and really the focus isto enable a small molecule drug design. And so we already have
all the viral proteinsfor expression and Nikolaiand we’re going through
them are currently,and we already have a number of crystalsfor some of the viral proteins. And so the idea here
is that by using thingslike fragment based, drug
design, drugs screening,and then computational drug designand visualizing those compounds foundwe can help that effort. The second prong, the second
part of their approachis really following up
strongly on the APMSand also actually on the functional datawhich will be coming in here. And so we narrowed down
this host proteins,which virus hijacks. We narrowed them down from
over 300 stories to about 60,which we think is the most
promising one based onthe biochemistry and the biological data. And we set up this sophisticated
system of approaching tags,expression purification,
who will be able to reallyvery rapidly screen for one
to five protein complexes,scales them up and
either do a purificationand go to prior electromicroscopy,
if it’s amenable,go to crystallography or even
uses novel affinity gridsfrom the argo group and skip
simplification altogetherand just go straight into the prior, yeah. And then the last part of it
is really is working togetherwith groups here at UCSF
for a focus of developingantibodies towards wild proteins,predominantly turns we
focused on spike proteinwith leveraging our consortium
strengths as expression. Purification and structural
biology to enablethem to just design better antibodies. And so, broadly altogether,
just to recap again as a plans,the goal is a three prong approach. On the left side is the idea
is to enable this rapid cycle. The turnover between the
chemists, the bioinformaticiansand the structural biologistswhere we get poor hits for the target,we get a structure was it, we
visualize and we see how wecan improve it based on the structure. We synthesize a new
candidate, and we repeat. The second one is focused on
something Nevan talked aboutis in the middle is
host directed therapies. And those are really exciting
because we can uncovercompeting new modalities of
being able to target these onesand frankly, again, as Nevan pointed out,because a lot of these are conservativecould be cross virus too. And last is the antibody effortwe think that we can destruct. Biology can play a major role
in being able to design morerationally higher identity
specificity antibodies,which could actually end
up being in the clinicand not too far future. And so we started out
about three weeks ago,and due to the incredible
dedication and hard workof the consortium members,we already have crystals for
a number of viral proteins. We already have a highest
resolution structurefor one of the viral proteins. And that’s on the left
and the bottom left panel,and then on the right we have,
you can see this gray box,the top quadrant is a
cry young roll micrographof a spike at the domain
with with antibodies foundand is being processed as we speak. And then on the bottom
is actually somethingwe just got today is the
first volume spike structurefrom the consortium at
betters in swing hamstrings. And again, these
structures have been solvedby other people before,
but this is an incrediblyimportant foundation
on which we can build. And we are already
building right as we speak,so there’s lots more to come. And that’s about it. – All right, fantastic, Klim. Thank you very much. Very good, great stuff. So, our last speaker of for
today is Shaeri Mukherjee. She’s leading up to protein
trafficking subgroup. And obviously protein trafficking
is a process that’s beinghijacked and utilized by
the virus and other viruses. And she’s been doing a fantastic
job extracting mechanisticinsight from this biological process. So, go ahead Shaeri- Can you see my slides?- I can see you, but not your slides. – Oh. – I think you have to share your screen. Yeah, we can see your slides now. – Good. Thanks Nevan. So, our group is mostly
interested in protein trafficking,and I would like to
start off by my thankingthe uprooting trafficking group. And here I’ve listed some
of the PIs who participatedin our Zoom calls and also the
trainees who have exchangedideas and thoughts
about how we can proceedwith understanding how the coronavirusco-ops the protein trafficking pathways. So, here I’m showing you
an intracellular snapshotof the coronavirus life-cycle. And there are two nodes of intersectionwith the Coronavirus, with
the host trafficking pathwaysthat we are mostly interested in. The first is when the spike
protein binds to the receptorof the host called ACE2,and this causes
internalization of the virus. And then the second is when
the virus has to assembleand egress out of the host cell. And more and more data is
starting to emerge that suggeststhat this assembly of the virus
takes place on the surfaceof a host cell organelles such
as the urgec and the golgi. Interestingly, when we looked
at the post translationalmodifications of several wild proteins,we notice that several of
them showed or linked or inletglycosylation as well as liquidation,such as farmetilization. And this suggested to us
that the virus did enterthe secretory organelles
because these enzymes are foundin the lumen of the secretory organelles. And very excitingly, a recent
paper in science that came outjust a few days ago
showed EM of SARS-CoV-2replication in organoids. And I was really excited
about how the golgi lookedin these images because you
could see the viral particleson the rim of the golgi,and the golgi appeared really swollen. And this suggested to me
that there might be an influxof protein and lipid
trafficking through the golgi. And it would be very interesting
to study how the virusco-ops this trafficking
pathways to maybe help itegress out of the host cell. Now, from the interactive
studies, when we analyze the hits,we found that roughly 40%
of protein interactorswere localized or function
in the secretory pathway. And 20 out of the 26 viral
proteins interact with at leastone secretory pathway protein. And this suggested to us that
the virus is really co-optingthe whole secretory pathway. And to understand these
interactions might give us betterunderstanding of the life
cycle of the coronavirusas well as figuring out how we can stop itfrom egressing out of the cell. Now how do we start from 132 proteins,and where do we even begin?So we thought instead of just
looking only for the hostproteins and seeing if they
have interesting functions,we could also start by
looking at the viral proteinsand seeing if they have
something interestingthat would point to a function. And the protein that we got very excitedabout is Orf8 in SARS-CoV-2. And this is a genome-wide
comparison of the SARS-CoV-2genome shown here in blue
versus several bad coronavirusgenomes as well as the SARS-CoV
genome from 2003 epidemic. And you can see here that this
is where the off Orf8 lies. And these spikes show
a fast evolving regionsuggesting many changes
happening in this region. And this is the spike
region also showing changes. This is expected because
it’s a surface protein,but this sounded really curious
what’s happening to Orf8. And if we compare the
two with the SARS-CoV-2with the SARS-CoV from 2003,
it’s only 30% conserved. And interestingly in the 2003 epidemicOrf8 originally encoded
a single polypeptide. But at the later stage of the epidemic,it underwent a 29 nucleotide deletion,which split Orf8 into
two Orfs of 8A and 8B. And later on it was shown
that just this step aloneled to the attenuation of the
virus replication in cells. So what’s happening to Orf8
in the current pandemic?So good news is that even
in this current pandemic,we have evidence that there is
a propensity of communicatingthis pot and a complete deletion of Orf8was not noticed in a
genome sequences of eighthospitalized patients in Singapore. So what’s known about Orf8
is that it seems to localizeto the endoplasmic reticulum
and induce ER stress. This is something that we
normally study in the lab,so we could use our expertise
to understand Orf8 is doingbecause even now the function
of Orf8 still remains unknown. So digging deep into the literatureand finding out what Orf8 could be doing. We found a very interesting
paper and this showed,this paper showed that Orf8 actuallyhas an immunoglobulin domain,
which is shared in anotherprotein called Orf7a, but this
is the immunoglobulin domainthat is in Orf7 and
this is what is in Orf8. And you can notice here that
there is an extra bit of uniqueinsert that is seen in Orf8
that is absent in Orf7. And this is modeled here,shown here in orange is the insert. And you’ll see here there’s
a Leu84 that seems to bethe most variable position
across 54 closely relatedSARS-CoV genomes. And these are bad Corona viruses. The top one is the SARS-CoV-2and the bottom is the SARS-CoV from 2003. So, the other interesting
difference was that Orf7had a transmembrane domain
attached to it afterthe immunoglobulin domain,
whereas the Orf8 does not. And interestingly, when the
Orf8 split into two proteinsin the 2003 later part of the endemic,this two proteins were
still could be linkedby a die cell fight bridge
suggesting that it would stillbe active, maybe not as active as Orf8. So, what is known about
Orf7 is that it bindsto the cell restriction factor BST-2and inhibits its glycosylation. And this impaired BST-2 with
tethering the plasma membraneimpaired antiviral response. So we are interested in
understanding how Orf8differs from Orf7 in the
sense that because it doesn’thave a transmembrane
domain can it be secretedout of the cell and
does that modify the waythe immune response happens?We are also interested in studying the ERbecause from the interim
studies you can see severalendoplasmic reticulum proteins
including stress responseprotein and ER degradation
pathway are hit. And interestingly, we also found hitfrom the ER membrane complex subunit EMC-1which has been known to
play a role in the spreadof flaming viruses such
as Zika and West Nile. So if this interaction is real,
it would be very interestingto understand the
function of Orf in the ER,of Orf8 in the ER. And finally, I would like to
also highlight another proteinin the virus NSP13. Why we are excited about NSP13
is because not only did itbind to the golgi
proteins and coiled-coiledstructural tethering proteins,including proteins that
have gripped domains,it also bound to the protein
Kinase A, signaling complex. And by complex I mean that it boundto not only the catalytic and
regulatory subunit of PKA,but also the scaffolding protein AKAP9as well as the protein that turns it off,which is the phosphodiesterase or PDE. So, we think that this
protein might be co-opting PKAsignaling at the golgi to
promote virus parting and spread. And this could change the way
the microtubule is nucleated. The other interesting aspect of NSB13is that it was found to bind to GCC185. This particular golgi binds
to 16 different Rab proteins. And Rab GTPases are known to play a rolein membrane trafficking. So this would be very exciting to studybecause the phenotype
of the golgi swellingand the fact that there could
be increased traffickingcould be explained if this
protein was somehow activatingalso a Rab GPS function. So, Brunno Goud who is a Curie Institutean expert of Rab reached out to us,and we are currently collaborating
to find that function. In addition, it’s good
news that PKA and PDEare both druggable targets. In a recent study showed
that PDE is actuallycan inhibit Corona viruses in retro. So with that I’d like to thank Nevanand the rest of the crew at QCRGas well as my two brilliant
postdocs, Advait and Julia. Advait is working on NSP13
and Julia is working on Orf8along with Albert in Melanie’s laband also our collaborators
in U. K and Curie. Thank you. – Thanks Shaeri. Awesome. Great stuff. I just have just a couple,
two wrap up slides here,just to make a point here that
QBI we’ve really been cryingover last several years
to break down silos. And I know this has
been a terrible tragedy,this particular pandemic,
but a silver lining for meis to see scientists
really around the worldcoming together in an unprecedented way. These silos have really been broken downacross laboratories, across
different institutions,between academia and
pharmaceutical companies,in a really unprecedented way. And my question is, why
can’t we do this normally?Look how fast science can move. And to me, the problem with
science is it’s too siloed. So the question is, can we
set up an infrastructure,really a new paradigm on how to do scienceso that we’re better prepared
for COVID-24, COVID-26what other other virus we want to work onor just working on any
disease for that matter. So, I would encourage the
community to really thinkalong these lines going forward. so we talked to you about thediscovery research, a component. We’re really gonna be
pushing hard now to connectto other entities at UCSF,
including the immunological worldand the clinical world. Hopefully the next QCRG town hall,we’ll talk about some of our
connections to these worlds. We’re really excited to push
or translate some of ourfindings into the clinical
world and we’re having numberof discussions with
different clinicians at UCSF. So stay tuned to that. And this is my last slide. We have a lot more
information on our websiteif you’d like to go and look
about the COVID-19 research. So, I’ll stop there and then I’ll letKayvon and Dave moderate questions. – Okay. I’ll take care of a couple of these,and Kayvon you’re welcome to
join in when you feel like it. The first one was came from Dave Egadand it’s directed mostly to
Davide who was talking aboutthese various anti translational
compounds and David Egadis curious to know how
toxic those compounds are. ‘Cause they looked a little
rough on the cell viabilityassays that you showed. So what do we know about their toxicityin those a cell-based assays?- Yes, thanks for the question. I didn’t go through in
the detail at that time. It’s not cytostatic, so
it doesn’t kill the cells. There is a cytostatic effect on the cellsand the reason it’s because the
cells are immortalized cellsand obviously they have non normal cellsand actually the viral
cells they have a mutationin a negative regulator soul cycle. So, they are really addicted
to proliferate more. And both of the compounds
are actually a target. Also the transmission of a key
mRNA porter for cell cycle. In the primary cells actually the cellspecific to these compounds
they’re not toxic. Ternatin as well as
zotatifin has been alsoused already then in mouse models. Zotatifin is already in the human. So, I think it’s the one already answeredthe question of toxicity. And also ternatin reject totally. We actually recently added
like very interesting datain the mouse model that the block tumorin a specific dose there
is no so much toxicity. – Okay. Thank you very much, sir. Next, there’s a couple of
questions here that are bothprobably for Brian Schoichet. And they’re all about the
sigma R-1 and R-2 receptors. Anita Seal is curious
to know which cell typesexpress these particular receptors,which obviously has an implication
for various other issues. And Sarah Kang is asking
a related question,which is what is the role
of the sigma-1 receptorand has it been implicated
in the infectionby any other viruses?- Okay, great question. So, that the sigma receptors
are most well knownbest characterized
neuronly, neuronal cells. That’s where most of the
work has been done on them,but they’re expressed, I
mean, tissue wise for sure,they’re expressed pretty ubiquitously,certainly in the lungs, for instance. As to the role of the sigma-1 receptorand whether it’s implicated
in other virus infections. It has a role in still
cell stress response. It’s thought to be active on activation. It forms a tremor in the inactive state. I only have two hands. This is a new discovery. It forms a tremor in the inactive state,and then it’s thought to monitorize. There’s good evidence for that. And when it gets activated and
then it acts as a chaperonewhen the cells are under stress. There’s actually good human
genetics that it’s importantfor neuron development. And then as to whether
it’s being implicatedin other viral infections?Yes, it has. Is not a large literature on
it, but both knock-down studieshave shown that it is involved,
you knock down the sigma-1receptor and viral infectivity will drop. Not, it’s not being done for SARS-2,but I think for HCV and one
other virus that I’m forgetting,but these are results
over the last decade. So there is some actually mechanisticand very logical reason
to believe that of coursesis pharmacology can be involved in. . . can be subverted by viruses generally. – Okay. I have another
question on the topic of drugs. Maybe Brian can do this or
maybe Nevan could do this. And that’s from David Earl
curious to know if you’ve begunto look for synergy between drugs. We’ve seen a lot of single
drugs in actions so are youstarting to combine them to see
what effect that might have?- I think everybody saw me texting outthat I was gonna answer David’s question,so maybe I can take a shot at it. So, I mean, it’s a great question. There’s actually ongoing tests
both in Paris and New Yorkadding one of the sigma-1 or
2 are the most promising one,the modulator with some of
these translational inhibitors,putting them together and
seeing what effects they have. Obviously, you got to
worry about toxicity,but then also remdesivir
combined with these. So just like with HIV, the cocktailwas the big breakthrough. And I personally think
a common trial strategyholds a lot of promise. Maybe combining this remdesivir
with one of our drugsor another drug that hits a host factorthat somebody else discovers. But then the big question is the resultsthat we see in the laboratory,do they translate into humans?I don’t know, going forward. I just wanted to answer,add something to Brian’s last comment. It was influenza, actually
Brian that was connectedto sigma-1. There was a genome wide RNE ice screenthat connected Sigma-1 to influenza. So there’s a connection there as well. So, that’s my response to David. I don’t know, Brian, if you
have anything to add to that. – No, I think that’s a. . . Yeah, so it’s influence and HCV, right?HCVL is also?- Yeah, Kayvon found that connection. – Nevan also Mary Selleck is
asking when we do the combos,do we think that orthogonal
targets will be betteror sort of in pathway might be better?That idea of where synergy
might pick us found?- Yeah, that’s a good question. I guess it’s related to
genetic interactions, right?I mean, it depends on
how much of one pathwayis ultimately perturbed. My thinking would be if you
had two different pathways,that would be a better approach. But you may have to worry
about toxicity there. So, it’s a great question,and more data needs to be collected. – I’ll try and take this next one. There’s a fairly complex
question here from Cynthia Chu. So, are there microscopy
data for cells treatedwith the Sigma ligand hits?From Nevan’s HPMS data set,
the Sigma receptor interactswith NSP-6 which is part
of a complex that formsa double membrane vesicles
seen in infected cells. So the question is whether
any of those compoundsthat affect the Sigma
receptor might actually affectthe membrane structures
of the secretory pathway. I don’t imagine that
you’ve gotten that far yet,but is there, is there a plan to do so?- Yeah, definitely. Actually, this morning we
just got some microscopy datafrom a collaborator in Germany
looking at certain kinasesthat are being mis-localized
in the context of infection. So I mean, yeah, that’s
a fantastic question is,especially in the context
of some of these drugs seenwhere some of these
viral proteins are goingor just see what’s happening
with the biology of the cell. There’s a lot of work to do going forward. – One last question about drugs again,they’re always about drugs
that from an anonymous attendeewho is curious to know, I suspect
I know the answer to this,but the question is whether
you can actually use plasmafrom a drug treated
human to test the effectof that on another patient. This sounds like a unusual idea. Is there any thoughts along those lines?Maybe Nevan, you should try that one. – I think. . . Oh, Davide, go ahead. – No, I think this already. . . So, the question, if a
plasma from already infectedpatients, if they can be used. So these are the question
or in combinationwith the drugs?’cause this has been— I think with the combination with drugs. Yeah, so it looks like
the idea of being. . . yeah, if that anonymous
attendee wants to clarifythe question, go ahead
and put it in the Q&A. but it looks like they’re referringto plasma from drug treated people. – Right, because that one
has been already startedto be used in the UK, in Italy. So, using the plasma from
infected people actuallyof course as enriched
in principle of courseof an antibiotic against the virus. But of course it can
be an interesting ideato also combine also with
some of the compoundsthat we described today. So, it can be interesting to think about. – Okay. We’ve got one more question
that just popped infrom Lisa for Klim. If they have plans to
look at the mutation,the recently discovered
mutation in spike protein,the D-614 gene mutation that
I guess was just associatedwith increased violence. We were actually talking about
this before this webinar. Is there any local lead,that structure worth looking at?- Yeah absolutely, actually. I was just looking at it
right before this meetingand it seems like it might
be at the interface betweenthe spike as a tremor,so you might be at the
interface between the monomers,but parts of the structure
I was looking at,there was a piece of it
which was disordered. So we don’t really see that
as part of acid packingor forming like a soul
bridge or something. But absolutely we should really look at itand see maybe, especially
with the antibody efforts,maybe the difference is there. It’s in the plan, it’s in the pipeline. – Okay. Oh no, a provocative
question has just shown up. It might be related to something
Nevan said in the newspaperactually which
is can Brian Schoichetcomment on the dextromethorphan issuein common flu and cold medication?Should you be taking that
medication at this point?- Yep Brian, go ahead. – I was gonna
defer to Nevan on this. – The only thing you could be sued for. – Yeah, Well I’m sure the
institution will protect me, Dave. So it’s a little bit worrying, right?Dextromethorphan looks pro
viral, reliably pro viral. That experiment was done more than once. What it means in terms of human health,I’d be very cautious to say,
but I think it does merita careful controlled trial. Whether that’s ethical
or not, I’m not sure. But I think the signal is. . . So, there’s a mechanistic reason,and there’s empirical evidence. And you put those two togetherand it’s enough to pay attention to. Yeah, that’s my answer. – Perfect, thank you. I think we’ve reached
the end of the questions,and we’ve reached 4:03. So, perhaps we could wrap this up. Obviously everyone out there
in the audience is welcometo email all these folks
anytime with further questionsand I’m sure they’d love to answer them. So, please do that. And thanks again for all
the wonderful presentations. Nevan, did you want to say one last wordor are you good to go?- Yup, sure. No, that’s fantastic. And we look forward to
ongoing QCRG town hallsand with other entities at UCSF,including the clinical worlds
and the immunological worlds. We’re very excited about that. – Great. Okay, thanks everyone for attending,we’ll see you next time. And as Lindsey mentioned,
there is another town halltomorrow as well on operational issuesabout how research is going at UCSF. So, we’ll see you there. Take care of everyone.

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