An Orally Available, Small-Molecule Polymerase Inhibitor Shows Efficacy Against a Lethal Morbillivirus Infection in a Large Animal Model

Abstract

Measles virus (MeV) is a highly infectious morbillivirus responsible for major human morbidity and mortality in the non-vaccinated. The related, zoonotic canine distemper virus (CDV) induces morbillivirus disease in ferrets with 100% lethality. We report an orally available, shelf-stable pan-morbillivirus inhibitor that targets the viral polymerase. Prophylactic oral treatment of ferrets infected intranasally with a lethal CDV dose reduced viremia and prolonged survival. Equally infected ferrets receiving post-infection treatment at the onset of viremia showed low-grade viral loads, remained asymptomatic and recovered from infection, while control animals succumbed to the disease. Recovered animals also mounted a robust immune response and were protected against re-challenge with a lethal CDV dose. Drug-resistant viral recombinants were generated and found attenuated and transmission impaired compared to the genetic parent. These findings pioneer a path towards an effective morbillivirus therapy that aids measles eradication by synergizing vaccine and therapeutics to close herd immunity gaps due to vaccine refusal.

Structure of the L Protein of Vesicular Stomatitis Virus from Electron Cryomicroscopy

“…For measles virus, resistance to a non-nucleoside analog inhibitor that blocks gene expression maps to the polymerase domain (Krumm et al, 2014). The positions of those mutations, mapped onto VSV-L, flank the GDNQ motif at the RdRp catalytic site, suggesting an allosteric mechanism, like that of the non-nucleoside analogue reverse transcriptase inhibitors for HIV.…”

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

“…Prophylaxis with the nucleoside inhibitor reduced the viral titer in vivo and prolonged survival; however, all 9 animals-those treated before infection and those with continued treatment throughout infection-eventually died (91). Surprisingly, efficacy was 100% in the 3 animals who were treated only 3 days postinfection (without prophylaxis) (91).…”

“…Prophylaxis with the nucleoside inhibitor reduced the viral titer in vivo and prolonged survival; however, all 9 animals-those treated before infection and those with continued treatment throughout infection-eventually died (91). Surprisingly, efficacy was 100% in the 3 animals who were treated only 3 days postinfection (without prophylaxis) (91). To explain these results, the authors posit that the postinfection treatment was effective because it allowed for a boost in immunity elicited by viral replication during the first 3 days but then prevented depletion of T and B lymphocytes (17,21,28,65).…”

Morbillivirus Experimental Animal Models: Measles Virus Pathogenesis Insights from Canine Distemper Virus

“…Furthermore, therapeutic interventions to control CDV infection may also be considered for valuable animals. Among the most promising candidates is an orally bioavailable small molecule inhibitor of the MeV polymerase that was able to rescue ferrets from lethal CDV challenge when given shortly after infection [90]. Strategies targeting viral entry or fusion, which also use small molecule inhibitors [91,92], as well as the first generation of host-targeting molecules [93], are reaching the state of preclinical testing, which will likely also involve one of the CDV surrogate models.…”