Next-generation direct-acting influenza therapeutics

Abstract

Influenza viruses are a major threat to human health globally. In addition to further improving vaccine prophylaxis, disease management through antiviral therapeutics constitutes an important component of the current intervention strategy to prevent advance to complicated disease and reduce case-fatality rates. Standard-of-care is treatment with neuraminidase inhibitors that prevent viral dissemination. In 2018, the first mechanistically new influenza drug class for the treatment of uncomplicated seasonal influenza in 2 decades was approved for human use. Targeting the PA endonuclease subunit of the viral polymerase complex, this class suppresses viral replication. However, the genetic barrier against viral resistance to both drug classes is low, pre-existing resistance is observed in circulating strains, and resistant viruses are pathogenic and transmit efficiently. Addressing the resistance problem has emerged as an important objective for the development of next-generation influenza virus therapeutics. This review will discuss the status of influenza therapeutics including the endonuclease inhibitor baloxavir marboxil after its first year of clinical use and evaluate a subset of direct-acting antiviral candidates in different stages of preclinical and clinical development.

Fig 1

Chemical structures of oseltamivir carboxylate, baloxavir marboxil, favipiravir, EIDD-2801, and pimodivir.

Fig 2

Principle of influenza virus inhibition by lethal mutagenesis induced by ribonucleoside analogs EIDD-2801 and T-705. In the absence of drug, random mutation frequency in the virus population is low (green). Sublethal concentrations of the inhibitor increase the frequency of random transition mutations, reducing overall fitness of the virus population (salmon). At sterilizing concentrations, the drug increases the random mutation frequency beyond a tolerable threshold, resulting in collapse of the virus population (red); MOA, mechanism of action. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)