In the creation of MAVDA, five projects with high translational potential were identified. These projects represent a diverse portfolio of targets and approaches to identify novel compounds resulting in validated Hits, early Leads, Leads suitable for immediate optimization, and Optimized Leads at or ready for IND-enabling and de-risking studies. A strong emphasis is placed on developing inhibitors against 3CLpro, the main protease that is pivotal for the replication of SARS-CoV-2, as a proven and highly desirable anti-viral target. In addition, other important targets include Nsp14 and Nsp16 MTase, ExoN, PLpro, Nsp13 helicase, RdRp, as well as novel targets. Two Projects have prominent industry partnerships, Merck and Takeda, and a third industry member, Aligos, leads a Project. All are committed to finding novel solutions to beat and preventing emerging viral threats. The list of projects and project leaders are listed below.

Project Project Lead Institution Title Company Target Status
1 Julian Symons Aligos Development of ALG-097558 as a broad-spectrum 3CL pro inhibitor Aligos 3CL pro Optimized Lead
2 David Perlin CDI Accelerated development of advanced leads againts SARS-CoV-2 and other pandemic viruses Merck 3CL pro Leads
3 Tom Tuschl Rockefeller Discovery of new antiviral protease and methylase inhibitors of corona-flavi, and alphaviruses Tri-I TDI Takeda 3CL pro; NSP14 Methylase; PL pro; Helicase Leads
4 Jingyue Ju Columbia Discovery and optimization of inhibitors for SARS-CoV-2 RNS synthesis TBD RdRp, Exonnuclease Early Leads
5 Alejandro Chavez, David Ho, Yossi Sabo Columbia - ADARC Multiplex small molecule discovery to identify broad-acting viral protease inhibitors TBD 3CL pro Hit to Lead

Project 1

Development of ALG-097558 as a broad-spectrum 3CL pro inhibitor
Four novel series of compounds with potent and selective SARS-CoV-2 3CLpro inhibition were identified with demonstrated broad-spectrum activity. This program is on track to move toward IND enabling studies.

Project Leader: Julian Symons, D.Phil.
Institution: Aligos Therapeutics
Location: South San Francisco, CA

Project 2

Accelerated development of advanced Leads against SARS-CoV-2 and other pandemic viruses

Boceprevir, an FDA-approved orally active serine protease inhibitor, is used to treat hepatitis C virus. Structure-based modeling combined with extensive medicinal chemistry mimicking the interactions of Boceprevir with the protease (3CLpro) structure in SARS-CoV-2 yielded lead compounds with exceptional therapeutic indices and forms the basis for this highly promising discovery effort that is producing Optimized Leads with selection for an IND enabling and de-risking program with Merck. The Optimized Lead Compounds will be evaluated against MERS, other coronaviruses and flaviviruses.

Project Leader: David Perlin, Ph.D.
Institution: Center for Discovery and Innovation, Hackensack Meridian Health
Industry Partner: Merck
Locations: Nutley, NJ; Kenilworth, NJ

Project 3

Discovery of new antiviral methylase, protease and helicase inhibitors of corona-, flavi-, and alphaviruses

Robust advanced hit-to-lead development program of inhibitors against SARS-CoV-2 PLpro and Nsp14 MTase, 3CLpro and Nsp13 helicase. Screening of inhouse (>430,000 member) RU library resulted in the identification of non-covalent hit-to-lead series of PLpro and Nsp14 inhibitors with promising translational potential. This project is highly robust and encompasses high-throughput screening and development of pre-lead and lead compounds. The compounds possess strong broad-spectrum potential and target viral proteases (3CLpro, PLpro), methylases (including 2’-O-MTase), and helicases in MERS, flavi- and alphaviruses.

Project Leader: Tom Tuschl, Ph.D.
Institution: Rockefeller University
Industry Partner: Tri-Institutional Therapeutics Discovery Institute - Takeda
Location: New York, NY

Project 4

Discovery and optimization of inhibitors for SARS-CoV-2 RNA synthesis

The Program uses synthetic chemistry, structural, functional and computational approaches to discover RNA polymerase (RdRp) and exonuclease (ExoN) inhibitors of SARS-CoV-2. Preliminary data support the thesis that simultaneous inhibition of both the viral RdRp and ExoN have synergistic effects in blocking SARS-CoV-replication. Implementing two high resolution molecular assays using mass-spectrometry detection to assess SARS-CoV-2 RdRp and ExoN activities for screening inhibitors and identified unique structure activity relationship information for inhibitors for RdRp and ExoN complexes. Based on this, new inhibitors with improved potency and reduced toxicity will be designed and synthesized. This project will develop early lead compounds (RdRp and ExoN inhibitors) with strong potential for broad-spectrum activity.

Project Leader: Jingyue Ju, Ph.D.
Institution: Columbia University
Industry Partner: TBD
Location: New York, NY

Project 5

Multiplex Small Molecule Discovery to Identify Broad-Acting Viral Protease Inhibitors

This program will utilize a novel approach to small molecule screening to uncover broadly active protease (CLpro) inhibitors against human and animal pathogens capable of studying >40 viral proteases at a time. An approach to in-depth resistance profiling was established to identify and optimize Leads that are not only potent and safe but for which viral escape is minimized. Tools produced are highly valuable to other programs.

Project Leaders: David Ho, Ph.D.; Alejandro Chavez, Ph.D.; Yosef Sabo, Ph.D.
Institution: Columbia University
Industry Partner: TBD
Location: New York, NY

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