Antiviral Agents: Structural Basis of Action and Rational Design

Abstract

During the last forty years, significant progress has been made in the development of novel antiviral drugs, mainly crystallizing in the establishment of potent antiretroviral therapies and the approval of drugs eradicating hepatitis C virus infection. Although major targets of antiviral intervention involve intracellular processes required for the synthesis of viral proteins and nucleic acids, a number of inhibitors blocking virus assembly, budding, maturation, entry, or uncoating act on virions or viral capsids. In this review, we focus on the drug discovery process while presenting the currently used methodologies to identify novel antiviral drugs by means of computer-based approaches. We provide examples illustrating structure-based antiviral drug development, specifically neuraminidase inhibitors against influenza virus (e.g., oseltamivir and zanamivir) and human immunodeficiency virus type 1 protease inhibitors (i.e., the development of darunavir from early peptidomimetic compounds such as saquinavir). A number of drugs acting against hepatitis B virus and human immunodeficiency virus and their mechanism of action are presented to show how viral capsids can be exploited as targets of antiviral therapy. The recent approval of the antiretroviral drug lenacapavir illustrates the successful application of this knowledge.

Keywords: Antiretroviral drugs; Capsid proteins; DNA polymerases; Drug development; Fusion inhibitors; Hepatitis virus; Herpesviruses; Human immunodeficiency virus; Influenza virus; Ligand docking; Neuraminidase; Nucleoside analogs; Proteases; Viral assembly; Viral entry; Viral replication; Virtual screening.