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Antiviral Agents: Structural Basis of Action and Rational Design

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

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

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Notes

  1. 1.

    Lipinski’s rule states that, in general, an orally active drug should meet at least three of the following criteria: (i) Not more than five hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms), (ii) not more than ten hydrogen bond acceptors (nitrogen or oxygen atoms), (iii) a molecular mass <500 daltons, and (iv) an octanol-water partition coefficient log P not greater than five.

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 Reading

  • Kazmierski WM (ed) (2011) Antiviral drugs: from basic discovery through clinical trials. Wiley, Hoboken

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  • LaFemina RL (ed) (2009) Antiviral research: strategies in antiviral drug discovery. ASM Press, Washington

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  • 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 are

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  • De Clercq E (2008) The discovery of antiviral agents: ten different compounds, ten different stories. Med Res Rev 28:929–953

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  • De Clercq E (2009) Antiviral drug discovery: ten more compounds, and ten more stories (part B). Med Res Rev 29:571–610

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  • De Clercq E (2009) Another ten stories in antiviral drug discovery (part C): “old” and “new” antivirals, strategies, and perspectives. Med Res Rev 29:611–645

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  • De Clercq E (2010) Yet another ten stories on antiviral drug discovery (part D): paradigms, paradoxes, and paraductions. Med Res Rev 30:667–707

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  • De Clercq E (2011) The next ten stories on antiviral drug discovery (part E): advents, advances, and adventures. Med Res Rev 31:118–160

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Acknowledgements

Work at CBMSO is supported in part by grants of the Spanish Ministry of Economy and Competitiveness (BIO2010/15542) and the General Directorate for Pharmacy and Medical Products (Ministry of Health, Social Services and Equality) (EC11-025), and an institutional grant from the Fundación Ramón Areces. Continued support to F.G. from the Spanish Comisión Interministerial de Ciencia y Tecnología (SAF2009-13914-C02-02) and Comunidad de Madrid (S-BIO/0214/2006 and S2010-BMD-2457) is gratefully acknowledged.

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Correspondence to Luis Menéndez-Arias or Federico Gago .

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Menéndez-Arias, L., Gago, F. (2013). Antiviral Agents: Structural Basis of Action and Rational Design. In: Mateu, M. (eds) Structure and Physics of Viruses. Subcellular Biochemistry, vol 68. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6552-8_20

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