Project 3 – Direct-Acting Antivirals against Paramyxoviruses

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The paramyxovirus (PMV) family contains some of the most contagious viruses known to infect humans such as measles (MeV) and mumps (MuV) virus, and some of the deadliest like Hendra (HeV) and Nipah (NiV) virus. The latter is listed on the WHO R&D blueprint as a pathogen of pandemic concern and has caused repeated deadly outbreaks when spilled over from bats into the human and animal populations. Bats are hosts to major mammalian paramyxoviruses, including the henipaviruses and other emerging pandemic threats. In support of our center’s (AC/DC) primary mission to develop orally available direct-acting clinical candidates against existing and emerging pandemic viral threats, Project 3 (P3) will test, characterize, and optimize the leading antiviral hits AC/DC has already discovered against paramyxoviruses of potential pandemic concern (P3CO). Our focus is on developing orally efficacious nucleoside analog and non-nucleoside RNA polymerase inhibitors. These target the conserved viral RNA-dependent RNA polymerase (RdRP) in mechanistically distinct ways and will ensure a pipeline of structurally diverse chemotypes active against P3CO. EIDD-2749 and GHP-88309 are exemplar NRPI and NNRPI chemotypes that are orally bioavailable, active against multiple genera of PMVs, have a wide safety margin (SI>500), favorable PK that allow for once or twice daily dosing, and have non-overlapping and fitness limiting resistance profiles. EIDD-2749 also has proven efficacy against SARS-CoV-2 (P1) and the viruses targeted by P5 and P6. These two compounds exemplify the hits that will drive the re-iterative chemotype-to- phenotype optimization and advanced characterization processes that underly the primary goal of P3, which is to develop orally bioavailable, structurally diverse, broad spectrum anti-PMV therapeutics with clinically and pharmacologically attractive properties that warrant formal IND development. Our driving hypothesis is that conserved structural and functional features of the PMV RdRP will allow for development of orally efficacious direct-acting antivirals. We will leverage the collective expertise and integrated resources of AC/DC (Cores A- F) to achieve our goal and test our hypothesis via the following four specific aims: we will characterize the efficacy parameters of nucleoside analogs as clinically relevant inhibitors of henipavirus replication (aim 1); we will develop non-nucleoside RNA polymerase inhibitors that target henipavirus replication complexes to complement or enhance nucleoside analog RNA polymerase inhibitor therapy (aim 2); we will evaluate the potential of both nucleoside analog and non-nucleoside RNA polymerase inhibitors as therapeutic drug candidates for morbilliviruses (aim 3); and we will discover new chemotypes that inhibit divergent paramyxovirus replication (aim 4).