Nucleoside Analogs with Antiviral Activity against Yellow Fever Virus

Abstract

Yellow fever virus (YFV) is a human Flavivirus reemerging in parts of the world. While a vaccine is available, large outbreaks have recently occurred in Brazil and certain African countries. Development of an effective antiviral against YFV is crucial, as there is no available effective drug against YFV. We have identified several novel nucleoside analogs with potent antiviral activity against YFV with 50% effective concentration (EC50) values between 0.25 and 1 μM with selectivity indices over 100 in culture.

Repurposing Nucleoside Analogs for Human Coronaviruses

“…Note that our group previously demonstrated that ALS-8112 is also an inhibitor of Nipah virus replication ( 15 ). Finally, 7-deaza-7-fluoro-2′- C -methyladenosine (compound 1), a nucleoside showing anti-yellow fever virus activity, was also evaluated ( 16 , 17 ). Remdesivir (compound 10) ( 18 ) and β- d - N 4 -hydroxycytidine (NHC; compound 17) were used as positive drug controls for these studies ( 19 ).…”

Anno 2021: Which antivirals for the coming decade?

“…Through in vitro screening of a small library of nucleoside analogues, 2’-methyl-7-deazaadenosine, 2’-methyl-7-fluoro-7-deazaadenosine, and a ProTide of 2’,2”-dichlorouridine were identified as effective inhibitors of YFV replication with EC 50 values in the 0.25–2.1 μM range and no cytotoxicity up to 100 μM. 158 …”

Disease Resurgence, Production Capability Issues and Safety Concerns in the Context of an Aging Population: Is There a Need for a New Yellow Fever Vaccine?

“…Currently, the most promising therapeutic agents in early clinical development are nucleoside analogs that inhibit viral RNA-dependent RNA polymerases [54][55][56][57][58]. For example, galidesivir has in vitro and in vivo activity against a broad range of RNA viruses, including Ebola, Marburg and YFV [58,59].…”

“…Numerous studies have identified other potential antiviral candidates; however, none have entered clinical trials. For example, sofosbuvir, a uridine analog used to treat hepatitis C, has shown antiviral activity against YFV in cell-based assays and rodent infection models [54,57]. Further preclinical development needs to be done for this and other candidates, and their clinical utility to treat YF remains untested.…”