PR97062

DarwinHealth Publishes Results of Novel, Viral Checkpoint-based Technology for Predicting Drugs that Inhibit SARS-CoV-2 Replication: Global Collaboration Highlights Generalizability of Reported ViroTreat Model for Host Cell-Directed Antiviral Drug Discovery, the Role of Master Regulator Proteins, and Application to other Viral Pathogens and Pandemic Response

NEW YORK, July 19, 2022 /PRNewswire=KYODO JBN/ --

DarwinHealth, Inc., a New York-based biotechnology and cancer drug discovery

company announces the July 19, 2022 online publication in Communications

Biology (a Nature Portfolio peer-reviewed journal) of a foundational paper

focused on new approaches to antiviral drug discovery, "A model for

network-based identification and pharmacological targeting of aberrant,

replication-permissive transcriptional programs induced by viral infection." (

https://www.nature.com/articles/s42003-022-03663-8)

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With the Covid pandemic still a significant issue in many countries—a situation

compounded by mounting concern about recurrent surges attributable to such

highly transmissible Omicron variants as BA.5, BA.2.75 and others—there remains

an unmet need for developing and deploying antiviral drug discovery models that

can accurately and expeditiously predict, validate, and leverage the potential

therapeutic effects of both established and investigational agents that inhibit

viral replication. This is especially the case for identifying antiviral drugs

that make infected host cells more resistant to viral infection—so-called

"host-directed therapy" or HDT—and, thereby, have the potential to be effective

as monotherapy or combination treatment to maximize the clinical effectiveness

of FDA-approved drugs targeting the virus directly through alternate mechanisms.

Against this backdrop, DarwinHealth scientists and their international

colleagues introduce and experimentally validate ViroTreat, a novel

integrative, regulatory network-based experimental model that can be deployed

for rapid identification of antiviral drugs targeting the host cell response to

viral hijack within a cell system-wide context. Specifically, the model

integrates both computational and experimental assays to: (a) identify

regulatory network aberrations, at the transcriptional level (the Viral

Checkpoint), induced by infecting viruses; and (b) predict drugs capable of

inhibiting viral replication and infectivity by counteracting the hijacking of

host cell regulatory mechanisms required for viral Infection.

In their report, the scientists noted that overall, 15 of the 18 drugs (83%)

predicted to be effective by their methodology induced significant reduction of

SARS-CoV-2 replication, without affecting cell viability. In contrast, none of

the 12 drugs selected as potential negative controls showed significant

antiviral effect. Drugs were prioritized for evaluation based on their

experimentally elucidated, context-specific mechanism of action determined by

drug perturbations in appropriately matched cell lines. This model for

host-directed pharmacological therapy is fully generalizable and can be

deployed to identify drugs targeting host cell-based master regulator

signatures induced by virtually any pathogen.

The publication is the result of a multi-institutional effort in search of an

efficient, precision-focused methodology for pursuing treatments for both

SARS-CoV-2 and a wide range of other viruses, and represents the outcome of an

international collaboration among scientists from the Department of Systems

Biology, Columbia University and the University of Florida (U.S.), the

Department of Infectious Diseases, Molecular Virology, Heidelberg University

(Germany), The Center for Precision Medicine, University of Bern (Switzerland),

and DarwinHealth, Inc. (U.S), which conceived and lead this global project.

"Against a challenging backdrop in which traditional drug screening approaches

and/or designing specific antivirals to address global pandemics are hampered

by either lack of precision or unacceptably long development periods,

respectively, the ViroTreat model we have developed can be seen as a chimeric

method in which we specifically target the host with small molecules that

render cells less permissive to viral infection and replication," explained

virologist Dr. Steeve Boulant, a lead author and Associate Professor,

Department of Molecular Genetics & Microbiology, University of Florida College

of Medicine. "Importantly, recent progress in organoid culture models, which

are functional 'mini-organs in a dish,' made it possible to secure

physiologically actionable data in the setting of SARS-CoV-2 infection, thereby

permitting us to deploy ViroTreat to quickly and predictably identify agents

that reduce infectivity. These advances make it possible to study both new and

existing viral pathogens, including influenza, in relevant organoid models in a

matter of only a couple of months, thereby expanding our toolkit with a

critical, new technology that will be invaluable for emerging pathogens, as

well as for existing viral diseases for which better and safer treatments

represent an unmet need."

The application of single cell analysis to improve the precision of antiviral

drug discovery was a key dimension of the model's experimental design. "Because

molecular analyses performed at the tissue level can easily produce

distorted/mixed signals generated by both infected and non-infected cells,

applying single-cell technology has been crucial for this work, explained lead

author, Dr. Pasquale Laise, Senior Director of Single Cells Systems

Pharmacology at DarwinHealth. "In this model, single cell technology permitted

us to clearly distinguish infected from non-infected cells, thereby uniquely

amplifying the transcriptional effects of SARS-CoV-2 on infected host cells.

This allowed our team to identify—in fact, quantify, using protein activity

levels assessed by our proprietary VIPER algorithm—the specific Viral

Checkpoint signature induced in the host by the virus; and, by extension,

reliably predict drugs that would inhibit replication during the viral hijack

phase of infection."

The results of this global effort identified a new approach for targeting

vulnerabilities of infective viruses that depart from conventional strategies

aimed at antiviral drug discovery. "This work demonstrates that

replication-permissive, viral hijacking of host cells is not limited to

exploiting the machinery required for ribonucleotide and protein synthesis—or

interference with innate antiviral immune responses—but goes deeper into the

mechanisms that regulate host cell transcriptional identity; in particular,

those inducing a host cell phenotypic state compatible with virus replication,"

explains Dr. Mariano Alvarez, CSO DarwinHealth. "Importantly, we show the

mechanisms regulating the hijacked cell transcriptional identity can be

dissected with precision. Moreover, pharmacological interventions, which we

predicted would block such transition, effectively locked cells into a viral

infection-refractory state. This approach may constitute a new paradigm for

efficiently identifying host-directed antivirals."

The group's success draws on technologies and models focused on cancer drug

discovery developed in the Califano Lab at Columbia University. "What is most

remarkable is that a methodology developed to study cancer cells and

developmental programs would work so effectively in prioritizing drugs for a

highly virulent infectious disease," emphasized Dr. Andrea Califano, Co-Founder

of DarwinHealth and Professor/Chair, Department of Systems Biology, Columbia

University

(https://news.columbia.edu/news/deciphering-cancer-messy-and-complex-were-here-i

t) "The generalizability of the approach suggests that this could lead to rapid

prioritization of treatments against other viral infections and future

pandemics."

"Until now, host cell-directed therapy (HDT) for viral infections has remained

elusive. To our knowledge, this is the first time an integrated experimental

and computational biological model of viral infection has been used to both

dissect and successfully target and reprogram the regulatory logic imposed on a

host cell by an infecting pathogen to facilitate viral hijacking," explained

Dr. Gideon Bosker, CEO and Co-Founder of DarwinHealth. "As such, our

proprietary R&D pipeline, based on VIPER technology, is ideally positioned to

be leveraged by biopharma partners to screen, discover and validate novel and

existing pharmacologic agents that, due to mechanisms conferring 'viral

contraception' at the host cell transcriptional level, can potentially be

therapeutically effective against a broad spectrum of viral infections.

Moreover, HDT-based approaches, such as the one we report, by directly

targeting multiple, validated host interactors, may mitigate vulnerability to

viral mutation-mediated alterations that potentiate immune evasion during

infection."

The DarwinHealth model reported in Communications Biology can be used as an

expeditious way to identify and screen established pharmacologic therapies with

low toxicity across a broad spectrum of mechanisms and viral

pathogens—including coronaviruses and influenza—to identify host cell-directed

therapies that may prove effective as either a direct, stand-alone intervention

or as a complementary approach to direct antiviral treatments, including

protease inhibitors and other agents.

"We believe the model we report—its methods, results, and

applications—represents an exciting experimental approach for dissecting

virus-host cell interactions that are amenable to pharmacologic targeting,"

added Dr. Bosker, "We anticipate broad interest among scientists working on

critical topics in host-microbe interactions and drug discovery in the context

of viral infections and emerging pandemics, for which accelerating the pace of

discovery and reducing costs associated with traditional drug development

processes are of paramount importance."

About DarwinHealth

DarwinHealth: Precision Therapeutics for Cancer Medicine is a "frontiers of

cancer," biotechnology-focused company, co-founded by CEO Gideon Bosker, MD,

and Professor Andrea Califano, Clyde and Helen Wu Professor of Chemical Systems

Biology and Chair, Department of Systems Biology at Columbia University. The

company's technology was developed by the Califano lab over the past 15 years

and is exclusively licensed from Columbia University.

DarwinHealth utilizes proprietary, systems biology algorithms to match

virtually every cancer patient with the drugs and drug combinations that are

most likely to produce a successful treatment outcome. "Conversely, these same

algorithms also can prioritize investigational drugs and compound combinations

of unknown potential against a full spectrum of human malignancies, as well as

novel cancer targets," explained Dr. Bosker, "which make them invaluable for

pharmaceutical companies seeking to both optimize their compound pipelines and

discover mechanistically actionable, novel cancer targets and compound-tumor

alignments."

DarwinHealth's mission statement is to deploy novel technologies rooted in

systems biology to improve clinical outcomes of cancer treatment. Its core

technology, the VIPER algorithm, can identify tightly knit modules of master

regulator proteins that represent a new class of actionable therapeutic targets

in cancer. The methodology is applied along two complementary axes: First,

DarwinHealth's technologies support the systematic identification and

validation of druggable targets at a more foundational, deep state of the

cancer cell's regulatory logic so we and our scientific partners can exploit

next generation actionability based on fundamental and more universal tumor

dependencies and mechanisms. Second, from a drug development and discovery

perspective, the same technologies are capable of identifying potentially

druggable novel targets based on master regulators, and upstream modulators of

those targets. This is where the DarwinHealth oncotectural approach, with its

emphasis on elucidating and targeting tumor checkpoints, provides its most

important solutions and repositioning roadmaps for advancing precision-focused

cancer drug discovery and therapeutics.

The proprietary, precision medicine-based methods employed by DarwinHealth are

supported by a deep body of scientific literature authored by its scientific

leadership, including DarwinHealth CSO, Mariano Alvarez, PhD, who co-developed

the company's critical computational infrastructure. These proprietary

strategies leverage the ability to reverse-engineer and analyze the genome-wide

regulatory and signaling logic of the cancer cell, by integrating data from in

silico, in vitro, and in vivo assays. This provides a fully integrated drug

characterization and discovery platform designed to elucidate, accelerate, and

validate precise developmental trajectories for pharmaceutical assets, so their

full clinical and commercial potential can be realized. For more information,

please visit: www.DarwinHealth.com .

CONTACT: Gideon Bosker, MD, CEO, DarwinHealth, Inc., Email:

GBosker@DarwinHealth.com, Phone: (1) 503-880-2207

SOURCE   DarwinHealth