Advancing a novel oral anti-IAV therapeutic to the clinic - ABSTRACT: Our overall objective is to develop a new class of direct acting antivirals (DAAs) against influenza A virus (IAV) infections, which can cause devastating pandemics of far greater mortality than COVID-19. Ideally, such therapeutics will be oral (for convenient outpatient use), a small molecule (for ease in manufacturing, storage, and distribution), of orthogonal mechanism of action (MOA) to currently available drugs (to maximize the potential for synergy with, or mitigating the development of resistance to, current therapeutics), and have demonstrated proof-of-concept in vivo efficacy against IAV in an animal model. Our preliminary data with our lead molecule, STF-8562, demonstrates that it meets all these criteria. In particular, our molecule’s MOA is distinct from Tamiflu, Baloxavir, and amantadine, and is fully active against IAV resistant to these three drugs. Our molecule targets the amphipathic helix (AH) motif in the IAV M2 protein, and provides 100% protection against a lethal inoculum of IAV in mice—even when administered 3 days after infection (at a time when Tamiflu and Baloxavir are ineffective). Moreover, we have developed two lead series that appear to target different aspects of the M2 AH, and are highly synergistic with each other. Thus, their optimization as proposed here can enable the best from one series to be nominated as the development candidate and the best of the second series to serve as back up as well as a possible synergistic partner. Finally, our latest leads have promising attributes for a successful IND, including no significant activity against hERG channels and good tolerability at high doses in rats. Although they could be developed as is, we hypothesize that: 1) our leads can be further optimized to enable once daily administration with a still lower dose; 2) our biochemical assay measuring the interaction of compound with its peptide target within IAV can assist with these efforts; 3) our knowledge of our leads’ major metabolites can guide optimization to increase in vivo metabolic stability; and 4) based on our current and to be obtained data, we can develop a successful IND package to enable an exciting new class of anti-IAV DAAs to enter the clinic. We propose to test these hypotheses via the following specific aims: 1) perform a focused medicinal chemistry effort to optimize our current lead molecules’ potency and pharmacokinetics to enable once daily dosing and nominate a lead inhibitor, and back-up molecule, to take into IND-enabling studies; 2) expand the virology data package by performing in vitro and in vivo selection for resistance studies, assessing efficacy against additional IAV strains, and performing combination experiments with other existing anti-IAV agents; 3) nominate an IND candidate by developing a process and analytical methods to manufacture non-GMP and GMP API, preparing an optimal formulation, and performing in vitro ADME-Tox, and non-GLP and GLP toxicity studies in rats and dogs; and 4) assemble an IND package to enable human clinical testing. Successful accomplishment of our aims will yield an exciting new class of oral small molecules--that we term M2AH--inhibitors, which can be used alone or in combination with other antivirals to counter seasonal and potential pandemic IAV strains.
