Value Of Drug Repurposing May Lie In Host-Directed Therapies – Bio-IT World

May10,2021|The pandemic hasshowcased thebest and the worst of the scientific enterprise, including thesilos that existbetween disciplines as well as the extraordinary speed of discovery when the barriers come down. Exhibit A comes from the University of California, San Francisco (UCSF), whoseQuantitative Biosciences Institute(QBI) spearheaded a six-nation collaborative around COVID-19 that now has 26 potential treatments in clinical trials.

The unprecedented level of cross-disciplinary teamwork, inclusive of 25 institutions and 10 industry partners, effectively unblinded researchersto commonalities across genes and disease areas, according to QBI DirectorNevanKrogan, Ph.D., who is also aprofessor in the department of cellular and molecular pharmacology. It will take concerted effort to maintainthatinfrastructure and spirit tobetter prepare forthenext pandemicor to find cures for perennial problems such asbreast cancerandAlzheimersdisease.

Drug repurposing has beenone of thefocal pointsof the QBICoronavirus Research Group(QCRG), both because time was of the essence and many anti-cancer drugs on the market proved effective againstCOVID-19,Krogansays. The same genes being mutated in cancer are being hijacked by SARS-CoV-2, just asAlzheimersdiseaseandtheZika virus share the same Achilles heel.

This is not terribly surprising, he adds, since viruses are very smart and evolved to attackcells. But scientists are going to miss the signs if they are not comparing notes.

Without coordination, both time and funding may be wasted, saysKrogan. Hundreds of repurposed drugs are now in clinical trials for COVID-19, but many of them work through a process calledphospholipidosis(a discovery madeby fellow QCRG scientist Brian Shoichet,DOI: 10.1101/2021.03.23.436648)thatlikely has no value in combatting the virus, he adds. Hydroxychloroquine falls in that category. Do we really need 450 clinical trials onhydroxychloroquineor just one?

Through the pandemic-inspiredAccelerating COVID19 Therapeutic Interventions and Vaccines (ACTIV) publicprivate partnership, the National Institutes of Health has been funding studies of repurposed drugs under a master protocol.Krogansays he applauds efforts like this byprioritizingthe drugs that get into clinical trials. We just need to see more of that.

Other recently reported collaborative efforts include alarge-scale humangenetics studyconducted by researchers from VA Boston Healthcare System, the University of Cambridge, EMBLs European Bioinformatics Institute,andIstitutoItaliano diTecnologiato identify drugstargetingIFNAR2 and ACE2 proteins that could be repurposed for early management of COVID-19 to prevent disease progression.

The artificial intelligence platform ofCyclicawas also deployed todiscover another potential COVID-19 drug from repurposingin this casecapmatinib(Tabrecta),Novartis MET inhibitorused to treat patientswith non-small cell lung cancerin a partnershipinvolvingRyerson University and the University of Torontos Vector Institute.

The real value in drug repurposing comes from targeting human proteins with host-directed therapies,Krogansays. Viruses mutate very quickly, but people dont. A virus is never going to mutate enough to overcome its reliance on human proteins to infect cells, reducing concerns about resistance.

So, while many pharmaceutical companies may opt to conduct largescale drug screens to identify repurposing candidates, QBI is sticking to its data-driven approach to drug discovery that starts with unraveling the underlying biology bydocumenting howthe proteins of a virus interactwithproteins in the cells of its target human host.

The approach takes alittle longer initially,butthelong-term consequencesare much more profound, saysKrogan. Our hit rateis much higher in terms of what is of value andweareso much further ahead in terms of tweaking the compound[for improved potency].

Protein Interaction Map

QBI created aHost-Pathogen Map Initiativejointly with the Center for Emerging and Neglected Disease at UC-Berkeley several years ago to create maps of the contact points betweenviral and human proteinsto understand how problem viruses like Ebola and Zika hijack, rewire, and infect human cells,Krogansays. But the pandemic enlarged the effort to more than 200 researchers worldwide singularly focused on finding drug candidates to wipe out infection by SARS-CoV-2.

The launch of QCRG began internally by establishing a web of interactions among over 40 uniquely skilled groups of scientists, which were broken into 12 subgroups specific to differentbiological processesand technologies, he says. Proteomics,cell biology,genetics,virology,structural biology,molecular biology,biochemistry,microscopy,bioinformatics, and clinical specialists all quickly came togetherpartially out of fearonly to learn how connected they really were.

As a first step, the QCRG constructed aSARS-CoV-2 protein interaction map revealing 66druggable human proteins or host factors targeted by 69 compoundsincluding 29 already approvedbytheFood and Drug Administration and another12 in clinical trials.The group is particularly excitedabout the potential of two translational inhibitors that were subsequently shown to be highly effective against SARS-CoV-2 in clinical trials conducted in New York and Paris.

One of the drugs, a translationalregulationinhibitor known aszotatifin(a product of EffectorTherapeuticsco-founded by UCSF scientists, including KevanShokat), has just been FDA-approved for aphase 1 clinical trialwith $5 million in funding from theDefense Advanced Research Projects Agency, he reports.Zotatifinis currently being tested in patients with solid tumors,andresults of preclinical studies showing itsin vitroantiviral activity against SARS-CoV-2were reported last spring inNature(DOI: 10.1038/s41586-020-2286-9).

The other drug,plitidepsin(Aplidin), approved by the Australian Regulatory Agency for the treatment of multiple myeloma, was found to be27.5-fold more potent against SARS-CoV-2 thanremdesivir,asreported earlier this year inScience(DOI: 10.1126/science.abf4058). Researchersdemonstrated prophylactic treatment reduced viral replication in the lungs of mice by two orders of magnitude.

PharmaMar has already launched aphase 3 clinical trialusingplitidepsinas a treatmentforpatients hospitalized for management of moderate COVID-19 infection,Krogansays. The study has been approved to run in 12 countries at 27 different sites.

Cancer drugs targetinghuman proteinsoften need to be taken formonthsoryears,he adds. Butas a treatment for acute infection by SARS-CoV-2, patients need only a short course ofplitidepsinfor a few days.

The challenge now is how to sustain large-scale collaborationswithscientistsneeding to resume work on projectsput onpausewhilethey were battlingCOVID, saysKrogan. But he is determined not to backtrack because science moves faster when everyone is working together,and scientist trainees also seem to learn better.

In addition to QCRG and the Host-Pathogen Map Initiative, UCSF is involved in aCancer Cell Map Initiativelooking atthemolecular networks(based on protein-protein and genetic interactions) underlying cancer, he notes. It also has aPsychiatric Cell Map Initiativeto elucidate thephysical and genetic interaction networksassociated withneuropsychiatric disorderssuch asautism and schizophrenia.

Bigdiscoveriesin the future are going to come from scientific collaborationlike theseacross disease and specialty areas,Krogansays. There isso much overlap therewejust dont[otherwise]appreciate.

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Value Of Drug Repurposing May Lie In Host-Directed Therapies - Bio-IT World