Abstract
Morbilliviruses, such as measles virus (MeV) and canine distemper virus (CDV), are highly infectious members of the paramyxovirus family. MeV is responsible for major morbidity and mortality in non-vaccinated populations. ERDRP-0519, a pan-morbillivirus small molecule inhibitor for the treatment of measles, targets the morbillivirus RNA-dependent RNA-polymerase (RdRP) complex and displayed unparalleled oral efficacy against lethal infection of ferrets with CDV, an established surrogate model for human measles. Resistance profiling identified the L subunit of the RdRP, which harbors all enzymatic activity of the polymerase complex, as the molecular target of inhibition. Here, we examined binding characteristics, physical docking site, and the molecular mechanism of action of ERDRP-0519 through label-free biolayer interferometry, photoaffinity cross-linking, and in vitro RdRP assays using purified MeV RdRP complexes and synthetic templates. Results demonstrate that unlike all other mononegavirus small molecule inhibitors identified to date, ERDRP-0519 inhibits all phosphodiester bond formation in both de novo initiation of RNA synthesis at the promoter and RNA elongation by a committed polymerase complex. Photocrosslinking and resistance profiling-informed ligand docking revealed that this unprecedented mechanism of action of ERDRP-0519 is due to simultaneous engagement of the L protein polyribonucleotidyl transferase (PRNTase)-like domain and the flexible intrusion loop by the compound, pharmacologically locking the polymerase in pre-initiation conformation. This study informs selection of ERDRP-0519 as clinical candidate for measles therapy and identifies a previously unrecognized druggable site in mononegavirus L polymerase proteins that can silence all synthesis of viral RNA.
Highlights
Morbilliviruses belong to the Paramyxoviridae family of highly contagious respiratory RNA viruses with negative polarity genomes
Measles is a vaccine-preventable disease, measles virus (MeV) remains responsible for approximately 100,000 deaths annually worldwide and endemic transmission persists in large geographical regions
Escape sites locate to the polymerase and capping domains of L, but notably do not overlap with the resistance profile of recently developed GHP-88309 [36], the only other well-characterized small molecule inhibitor of MeV L (Fig 1A)
Summary
Morbilliviruses belong to the Paramyxoviridae family of highly contagious respiratory RNA viruses with negative polarity genomes. The archetype of the morbillivirus genus, MeV, is the most infectious pathogen identified to date with primary reproduction rates of 12–18 [1,2]. Measles is a vaccine-preventable disease, MeV remains responsible for approximately 100,000 deaths annually worldwide and endemic transmission persists in large geographical regions. Due to its exceptional contagiousness, MeV is typically the first pathogen to reappear when vaccination coverage drops in an area [3,4]. In the aftermath of parental concerns about vaccination safety, four European countries, Albania, Czechia, Greece and the United Kingdom, have regressed to pre-measles eradication status [5]. A massive surge in global measles cases is feared as a result of the SARS-CoV-2 pandemic, since immunization campaigns have been suspended as part of the COVID-19 response [6,7,8]. Effective anti-MeV therapeutics may aid by providing avenues to improved disease management and rapid outbreak control [9]
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