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.
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- 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.
- 2.
Also especially recommended for further reading are references [1, 3, 18, 35] listed above.
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
LaFemina RL (ed) (2009) Antiviral research: strategies in antiviral drug discovery. ASM Press, Washington
Young DC (2009) Computational drug design: a guide for computational and medicinal chemists. Wiley, Hoboken
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
De Clercq E (2008) The discovery of antiviral agents: ten different compounds, ten different stories. Med Res Rev 28:929–953
De Clercq E (2009) Antiviral drug discovery: ten more compounds, and ten more stories (part B). Med Res Rev 29:571–610
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
De Clercq E (2010) Yet another ten stories on antiviral drug discovery (part D): paradigms, paradoxes, and paraductions. Med Res Rev 30:667–707
De Clercq E (2011) The next ten stories on antiviral drug discovery (part E): advents, advances, and adventures. Med Res Rev 31:118–160
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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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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