Structure and Physics of Viruses pp 599-630

Part of the Subcellular Biochemistry book series (SCBI, volume 68)

Antiviral Agents: Structural Basis of Action and Rational Design

Chapter

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 

Abbreviations

AIDS

Acquired immune deficiency syndrome

CoMFA

Comparative molecular field analysis

CTD

C-terminal domain

HBV

Hepatitis B virus

HCMV

Human cytomegalovirus

HCV

Hepatitis C virus

HIV

Human immunodeficiency virus

HR

Heptad repeat

HSV

Herpes simplex virus

HTS

High-throughput screening

LBVS

Ligand-based virtual screening

mRNA

Messenger RNA

Neu5Ac

N-acetylneuraminic acid

NMR

Nuclear magnetic resonance

NNRTIs

Nonnucleoside RT inhibitors

NTD

N-terminal domain

PDB

Protein Data Bank

RSV

Respiratory syncytial virus

RT

Reverse transcriptase

SBVS

Structure-based virtual screening

THF

Tetrahydrofuran

VZV

Varicella-zoster virus

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Further Reading2

  1. Kazmierski WM (ed) (2011) Antiviral drugs: from basic discovery through clinical trials. Wiley, HobokenGoogle Scholar
  2. LaFemina RL (ed) (2009) Antiviral research: strategies in antiviral drug discovery. ASM Press, WashingtonGoogle Scholar
  3. Young DC (2009) Computational drug design: a guide for computational and medicinal chemists. Wiley, HobokenCrossRefGoogle Scholar
  4. A collection of reviews written by Dr. Eric De Clercq and published in Medicinal Research Reviews between 2008 and 2011 provide a nice summary on the design and development of many antiviral drugs, from a historical perspective and providing relevant chemical structures. References for these articles areGoogle Scholar
  5. De Clercq E (2008) The discovery of antiviral agents: ten different compounds, ten different stories. Med Res Rev 28:929–953PubMedCrossRefGoogle Scholar
  6. De Clercq E (2009) Antiviral drug discovery: ten more compounds, and ten more stories (part B). Med Res Rev 29:571–610PubMedCrossRefGoogle Scholar
  7. De Clercq E (2009) Another ten stories in antiviral drug discovery (part C): “old” and “new” antivirals, strategies, and perspectives. Med Res Rev 29:611–645PubMedCrossRefGoogle Scholar
  8. De Clercq E (2010) Yet another ten stories on antiviral drug discovery (part D): paradigms, paradoxes, and paraductions. Med Res Rev 30:667–707PubMedGoogle Scholar
  9. De Clercq E (2011) The next ten stories on antiviral drug discovery (part E): advents, advances, and adventures. Med Res Rev 31:118–160PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Centro de Biología Molecular “Severo Ochoa” (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid)MadridSpain
  2. 2.Department of PharmacologyUniversidad de AlcaláMadridSpain

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