Research conducted by MassCPR-funded investigators closely mirrored leading edge efforts and global priorities to rapidly develop therapeutics against SARS-CoV-2 from the early stages of the pandemic and onwards. Research included efforts to target viral proteases with small molecules (Namchuk), efforts to target the SARS-CoV-2 spike protein with monoclonal antibodies (Abraham, Harrison, and Marasco), and efforts to rapidly test a small molecule that targets viral replication in a Phase 2 clinical trial (Juelg).

Important findings came from efforts to develop small molecule inhibitors of the SARS-CoV-2 main (Mpro) and papain-like (PLpro) proteases (Namchuk). As with other efforts by MassCPR investigators, the performed work was highly mechanistic and will have broader implications to drug design, including providing a better structural understanding of viral protease substrate specificities (Namchuk).

Important findings also included identification of neutralizing antibodies that target the SARS-CoV-2 spike protein isolated from the blood of COVID-19 convalescent donors or using phage display (Abraham, Harrison, and Marasco). These projects resulted in the isolation of large panels of antibodies that were rapidly tested for activity against SARS-CoV-2 variants as they emerged. This work resulted in X-ray crystallographic and cryo-electron microscopy structures of the SARS-CoV-2 spike protein complexed with the antigen binding fragments of neutralizing antibodies, providing critical insight into the design of next-generation monoclonal antibodies that are resilient against antibody escape mutations.

Additional projects included platform development for cutting-edge tools to better study SARS-CoV-2 molecular and cellular pathogenesis and guide therapeutic development (Luban and Rajagopal), and efforts to broaden our understanding of how innate immune pathways may be harnessed to broadly inhibit replication of RNA viruses (Fitzgerald). The Fitzgerald effort also included forward-thinking work on additional therapeutic modalities (RNA-based therapeutics) that are not currently used as agents in the clinic and had promising results in cell-based assays.

Work on therapeutics within the consortium spanned from basic research to therapeutic application. MassCPR-funded work by Juelg allowed for the first randomized Phase 2 trial of favipiravir against SARS-CoV-2 in the United States. This demonstrated the nascent and exciting potential for collaborative work done within MassCPR to extend to evaluation in humans of therapeutic candidates developed within the consortium.

The data obtained from within the Therapeutics Working Group, and overall outcomes of therapeutics research for COVID-19, make similar suggestions for subsequent research and pandemic preparation. Broadly speaking, this can be divided into tools and therapies, and therapies can be divided into repurposing and de novo drug discovery. 

It needs to be acknowledged that the bar for development of a viable antiviral is very high, requiring maintenance of clinical exposure exceeding the EC₉₀ for the compound in cells, corrected for serum free fraction, to exert a therapeutically useful effect. In the case of repurposing of approved agents, this needs to occur at the previously approved dose to ensure the safety profile of the compound can be retained. To date, no host cell targeted approach has made this bar, and this should be applied to set a bar for future host cell targeted antivirals and direct acting antivirals.

MassCPR pursued several parallel strategies for de novo drug discovery, including siRNAs, small molecule drug discovery, and antibody therapeutics.  Small molecule therapeutic discovery is not at critical mass within the MassCPR ecosystem and is likely better pursued by individual labs in collaboration with corporate partners (the AbbVie collaboration is a good example). As outlined in the Fitzgerald proposal, alternative modalities such as siRNA remain somewhat underexplored and could hold promise, in particular in less acute infections. A critical factor in determining whether such platforms could be of broad utility for the next pandemic will require assessment of several practical issues: importantly, can such a therapeutic be dosed to provide adequate viral suppression to be of likely utility in reducing disease.

A clear area of strength of the MassCPR community is antibody generation and rapid characterization. Both the Abraham and Maracsco labs (and others, for example, the Alter lab) have tremendous capabilities in generation of potential therapeutic antibodies, and knitting these labs and others to work in a coordinated manner to prepare for the next pandemic would be of great utility. Another clear strength of the community was in the ability to provide structural insights, in a rapid fashion, to understand emerging resistance to antibody therapies as the pandemic progressed and to inform (Abraham and Harrison, plus others at HMS). For SARS-CoV-2, the rapid obsolescence of antibody therapies limited therapeutic options throughout the early phase of the pandemic. It would be extraordinarily enabling to further develop and maintain a robust, rapidly deployed structural biology consortium to drive both the provision of reagents for the community and the mapping of the likely trajectory of emergent resistance for future pandemic pathogens. Said in a different way, can we design second generation antibodies first, using the roadmap created with SARS-CoV-2? One clear recommendation would be to create an antibody center of excellence for future pandemics. Integrating this effort with corporate partners to rapidly progress these discoveries to the clinic would be a powerful engine of discovery to combat future pandemics.