Chapter

Structure and Physics of Viruses

Volume 68 of the series Subcellular Biochemistry pp 599-630

Date:

Antiviral Agents: Structural Basis of Action and Rational Design

  • Luis Menéndez-AriasAffiliated withCentro de Biología Molecular “Severo Ochoa” (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid) Email author 
  • , Federico GagoAffiliated withDepartment of Pharmacology, Universidad de Alcalá Email author 

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Abstract

During the last 30 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 inhibiting hepatitis C virus replication. 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 using a computer-based approach. 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 in preclinical development acting against picornaviruses, 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.

Keywords

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