Online citations, reference lists, and bibliographies.
← Back to Search

Strategies In The Design Of Antiviral Drugs

E. De Clercq
Published 2002 · Medicine

Cite This
Download PDF
Analyze on Scholarcy
Key PointsGreater understanding of viral life cycles has resulted in the discovery and validation of several targets for therapeutic intervention, and an increase in the number of antiviral drugs from 5 in 1990 to over 30 in 2001. However, there is considerable room for improvement, as these compounds are not always efficacious (owing to virus resistance) or well tolerated.Antiviral drug design could, in principle, be targeted at either viral proteins or cellular proteins. The first approach is likely to yield more specific, less toxic compounds, with a narrow spectrum of antiviral activity and a higher likelihood of resistance developing. The second approach might afford antiviral compounds with a broader activity spectrum and less chance of resistance developing, but higher likelihood of toxicity.Some stages in the viral life cycle that can, or could, be targeted by drugs include virus adsorption, virus–cell fusion, viral DNA or RNA synthesis and viral enzymes, such as HIV protease and influenza virus neuraminidase. Two host cellular enzymes, inosine 5′-monophosphate dehydrogenase and S-adenosylhomocysteine hydrolase, could also be targets for certain classes of antiviral agents.Licensed drugs include:Inhibitors of viral DNA polymerases: nucleoside analogues such as acyclovir, and acyclic nucleoside phosphonates such as cidofovir.Inhibitors of HIV reverse transcriptase: nucleoside reverse transcriptase inhibitors such as azidothymidine, non-nucleoside reverse transcriptase inhibitors such as nevirapine, and acyclic nucleoside phosphonates such as tenofovir and adefovir.Inhibitors of HIV protease, such as indinavir.Inhibitors of influenza virus neuraminidase, such as zanamivir.IMP dehydrogenase inhibitors, such as ribavirin and mycophenolic acid.Drugs in development that are not in the above classes include:Inhibitors of virus adsorption, such as polyanions.Inhibitors of virus–cell fusion, such as AMD3100, TAK779 and T20.Inhibitors of human rhinovirus proteases, such as AG7088.AbstractA decade ago, just five drugs were licensed for the treatment of viral infections. Since then, greater understanding of viral life cycles, prompted in particular by the need to combat human immunodeficiency virus, has resulted in the discovery and validation of several targets for therapeutic intervention. Consequently, the current antiviral repertoire now includes more than 30 drugs. But we still lack effective therapies for several viral infections, and established treatments are not always effective or well tolerated, highlighting the need for further refinement of antiviral drug design and development. Here, I describe the rationale behind current and future drug-based strategies for combating viral infections.
This paper references
update and perspectives
Y. Pommier (2000)
Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection
D. Mendel (1998)
Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: towards smaller inhibitors.
M. Llinàs-Brunet (2000)
Mutational analysis of trp-229 of human immunodeficiency virus type 1 reverse transcriptase (RT) identifies this amino acid residue as a prime target for the rational design of new non-nucleoside RT inhibitors.
H. Pelemans (2000)
The cyclohexene ring system as a furanose mimic: synthesis and antiviral activity of both enantiomers of cyclohexenylguanine.
J. Wang (2000)
SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo
J. Strizki (2001)
Enzymatic properties of hepatitis C virus NS3-associated helicase.
C. Paolini (2000)
Inhibiting HIV-1 Entry Discovery of D-Peptide Inhibitors that Target the gp41 Coiled-Coil Pocket
D. Eckert (1999)
A general model for the surface glycoproteins of HIV and other retroviruses.
W. Gallaher (1995)
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 1. Michael acceptor structure-activity studies.
P. Dragovich (1998)
towards smaller inhibitors
Llinàs-Brunet (2000)
RNA virus error catastrophe: Direct molecular test by using ribavirin
S. Crotty (2001)
4-Hydroxy-5,6-dihydropyrones as Inhibitors of HIV Protease: The Effect of Heterocyclic Substituents at C-6 on Antiviral Potency and Pharmacokinetic Parameters.
S. Hagen (2001)
A novel selective broad-spectrum anti-DNA virus agent
E. Clercq (1986)
Design and synthesis of pyrrolidine5,5-trans-lactams (5-oxo-hexahydro-pyrrolo[3,2-b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease
Borthwick (2000)
Novel Approaches to the Treatment of Hepatitis C Virus Infection
B. W. Dymock (2000)
The identification of α-ketoamides as potent inhibitors of hepatitis c virus nS3-4a proteinase
J. M. Bennett (2001)
Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells.
D. Hazuda (2000)
Herpes Simplex Virus Type 1 Entry Is Inhibited by the Cobalt Chelate Complex CTC-96
J. A. Schwartz (2001)
The Novel Immunosuppressive Agent Mycophenolate Mofetil Markedly Potentiates the Antiherpesvirus Activities of Acyclovir, Ganciclovir, and Penciclovir In Vitro and In Vivo
J. Neyts (1998)
Design and synthesis of lipophilic phosphoramidate d4T-MP prodrugs expressing high potency against HIV in cell culture: structural determinants for in vitro activity and QSAR.
A. Siddiqui (1999)
Protease Inhibitors as Antiviral Agents
A. Patick (1998)
Characterization of the activation pathway of phosphoramidate triester prodrugs of stavudine and zidovudine.
D. Saboulard (1999)
In Vitro Antiviral Activity of AG7088, a Potent Inhibitor of Human Rhinovirus 3C Protease
A. Patick (1999)
Broad-Spectrum Antiviral Activity of the IMP Dehydrogenase Inhibitor VX-497: a Comparison with Ribavirin and Demonstration of Antiviral Additivity with Alpha Interferon
W. Markland (2000)
Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry
J. Michael Kilby (1998)
Structure - based design , synthesis , and biological evaluation of irreversible human rhinovirus 3 C protease inhibitors . 2 . Peptide structure – activity studies
P. S. Dragovich (1998)
Cyclopentane Neuraminidase Inhibitors with Potent In Vitro Anti-Influenza Virus Activities
D. Smee (2001)
Inhibition of herpes proteases and antiviral activity of 2-substituted thieno[2,3-d]oxazinones.
R. L. Jarvest (1999)
Synthesis and antiviral activity of monobactams inhibiting the human cytomegalovirus protease.
W. Ogilvie (1999)
Cyclosaligenyl-2 9 , 3 9-didehydro-2 9 , 3 9-dideoxythymidine Monophosphate : Efficient Intracellular Delivery of d 4 TMP
J. Balzarini (2000)
Mutation of Asp(171) and Asp(262) of the chemokine receptor CXCR4 impairs its coreceptor function for human immunodeficiency virus-1 entry and abrogates the antagonistic activity of AMD3100.
S. Hatse (2001)
Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections
Hayden (1997)
Design and synthesis of pyrrolidine-5,5-trans-lactams (5-oxo-hexahydro-pyrrolo[3,2-b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 1. The alpha-methyl-trans-lactam template.
A. D. Borthwick (2000)
Poly(sodium 4-styrene sulfonate): an effective candidate topical antimicrobial for the prevention of sexually transmitted diseases.
B. Herold (2000)
Antiviral activities of 5-ethynyl-1-beta-D-ribofuranosylimidazole-4- carboxamide and related compounds.
E. De Clercq (1991)
Structure-assisted design of mechanism-based irreversible inhibitors of human rhinovirus 3C protease with potent antiviral activity against multiple rhinovirus serotypes.
D. A. Matthews (1999)
Inhibition of T-tropic HIV Strains by Selective Antagonization of the Chemokine Receptor CXCR4
D. Schols (1997)
Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment.
F. Hayden (1999)
Resistance of the human immunodeficiency virus to the inhibitory action of negatively charged albumins on virus binding to CD4.
C. Cabrera (1999)
Comparison of the Anti-Influenza Virus Activity of RWJ-270201 with Those of Oseltamivir and Zanamivir
S. Bantia (2001)
Therapeutic potential of HPMPC as an antiviral drug
E. Clercq (1993)
Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate
Y. Chen (1997)
Mode of Action of (1′S,2′R)-9-{[1′,2′-Bis(hydroxymethyl) cycloprop-1′-yl]methyl}guanine (A-5021) against Herpes Simplex Virus Type 1 and Type 2 and Varicella-Zoster Virus
N. Ono (1998)
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements.
P. Dragovich (1999)
cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system.
C. Meier (1998)
HIV-1 Integrase as a Target for Antiviral Drugs
Y. Pommier (1997)
A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever.
M. Bray (1998)
4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells.
J. Wai (2000)
NS3 serine protease of bovine viral diarrhea virus: characterization of active site residues, NS4A cofactor domain, and protease-cofactor interactions.
N. Tautz (2000)
Human immunodeficiency virus glycoprotein gp120 as the primary target for the antiviral action of AR177 (Zintevir).
J. Esté (1998)
A randomized 4‐arm multicenter study of interferon alfa–2b plus ribavirin in the treatment of patients with chronic hepatitis C not responding to interferon alone
G. Saracco (2001)
Treatment of lethal Ebola virus infection in mice with a single dose of an S-adenosyl-L-homocysteine hydrolase inhibitor.
M. Bray (2000)
Binding of the Second Generation Non-nucleoside Inhibitor S-1153 to HIV-1 Reverse Transcriptase Involves Extensive Main Chain Hydrogen Bonding*
J. Ren (2000)
Only a small fraction of purified hepatitis C RNA-dependent RNA polymerase is catalytically competent: implications for viral replication and in vitro assays.
S. S. Carroll (2000)
Zanamivir Susceptibility Monitoring and Characterization of Influenza Virus Clinical Isolates Obtained during Phase II Clinical Efficacy Studies
J. M. Barnett (2000)
The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen
S. Crotty (2000)
Vaccinia Virus Inhibitors as a Paradigm for the Chemotherapy of Poxvirus Infections
E. de Clercq (2001)
Protein Design of an HIV-1 Entry Inhibitor
M. Root (2001)
Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity.
C. U. Kim (1997)
Structure and Mechanism of Inosine Monophosphate Dehydrogenase in Complex with the Immunosuppressant Mycophenolic Acid
M. Sintchak (1996)
The inhibition of human cytomegalovirus (hCMV) protease by hydroxylamine derivatives.
D. Smith (1999)
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors
Dragovich (1998)
Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial
KG Nicholson (2000)
Inhibition of HIV infection by bicyclams, highly potent and specific CXCR4 antagonists.
E. Clercq (1999)
Human Immunodeficiency Virus Gene Regulation as a Target for Antiviral Chemotherapy
D. Daelemans (1999)
Broad-spectrum antiviral activities of neplanocin A, 3-deazaneplanocin A, and their 5'-nor derivatives.
E. De Clercq (1989)
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics.
P. Dragovich (1999)
Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class.
S. R. Turner (1998)
Selective nonpeptidic inhibitors of herpes simplex virus type 1 and human cytomegalovirus proteases.
M. Matsumoto (2001)
A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity.
M. Baba (1999)
The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection
E. Clercq (1998)
Arylalkylidene rhodanine with bulky and hydrophobic functional group as selective HCV NS3 protease inhibitor.
W. T. Sing (2001)
Models which explain the inhibition of reverse transcriptase by HIV-1-specific (thio)carboxanilide derivatives.
R. Esnouf (1997)
A second target for the peptoid Tat/transactivation response element inhibitor CGP64222: inhibition of human immunodeficiency virus replication by blocking CXC-chemokine receptor 4-mediated virus entry.
D. Daelemans (2000)
In Vivo Influenza Virus-Inhibitory Effects of the Cyclopentane Neuraminidase Inhibitor RWJ-270201
R. Sidwell (2001)
an effective candidate topical antimicrobial for the prevention of sexually transmitted diseases
Herold (2000)
A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5.
T. Dragic (2000)
Viral entry as the primary target for the anti-HIV activity of chicoric acid and its tetra-acetyl esters.
W. Pluymers (2000)
An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication.
F. Hamy (1997)
Antiherpesvirus Activities of (1′S,2′R)-9-{[1′,2′-Bis(hydroxymethyl)cycloprop-1′-yl]methyl}guanine (A-5021) in Cell Culture
S. Iwayama (1998)
Development of resistance of human immunodeficiency virus type 1 to dextran sulfate associated with the emergence of specific mutations in the envelope gp120 glycoprotein.
J. Esté (1997)
Rational design of potent sialidase-based inhibitors of influenza virus replication
M. Itzstein (1993)
Intracellular metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylmethoxyethyl)adenine, a potent anti-human immunodeficiency virus compound.
J. Balzarini (1991)
Flavopiridol Inhibits P-TEFb and Blocks HIV-1 Replication*
S. Chao (2000)
Highly potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain.
C. Mcguigan (2000)
Antiviral drug therapy of filovirus infections: S-adenosylhomocysteine hydrolase inhibitors inhibit Ebola virus in vitro and in a lethal mouse model.
J. Huggins (1999)
Retroviral integrase inhibitors year 2000: update and perspectives.
Y. Pommier (2000)
efficient intracellular delivery of d4TMP
Balzarini (2000)
Structural mechanisms of HIV drug resistance.
J. Erickson (1996)
Potent and selective inhibition of varicella-zoster virus (VZV) by nucleoside analogues with an unusual bicyclic base.
C. Mcguigan (1999)
The Herpesvirus Proteases as Targets for Antiviral Chemotherapy
L. Waxman (2000)
randomized controlled trials for prevention and treatment
Hayden (1999)
Inhibition of human immunodeficiency virus type 1 replication and cytokine production by fluoroquinoline derivatives.
M. Baba (1998)
Inhibition of Acute-, Latent-, and Chronic-Phase Human Immunodeficiency Virus Type 1 (HIV-1) Replication by a Bistriazoloacridone Analog That Selectively Inhibits HIV-1 Transcription
J. Turpin (1998)
Peptides from conserved regions of paramyxovirus fusion (F) proteins are potent inhibitors of viral fusion.
D. Lambert (1996)
Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity.
D. Margolis (1999)
a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6dihydro-4-hydroxy-2-pyrone sulfonamide class
Turner (1998)
A Novel Role for 3-O-Sulfated Heparan Sulfate in Herpes Simplex Virus 1 Entry
D. Shukla (1999)
Antiviral drugs: current state of the art.
E. De Clercq (2001)
Influenza Neuraminidase Inhibitors Possessing a Novel Hydrophobic Interaction in the Enzyme Active Site: Design, Synthesis, and Structural Analysis of Carbocyclic Sialic Acid Analogues with Potent Antiinfluenza Activity.
C. U. Kim (1997)
Effect of incorporation of cidofovir into DNA by human cytomegalovirus DNA polymerase on DNA elongation.
X. Xiong (1997)
The HIV‐1 Reverse Transcription (RT) Process as Target for RT Inhibitors
H. Jonckheere (2000)

This paper is referenced by
A novel thymidylate synthase from the Vibrionales, Alteromonadales, Aeromonadales, and Pasteurellales (VAAP) clade with altered nucleotide and folate binding sites
Alonso A Lopez-Zavala (2018)
Understanding infectious agents from an in silico perspective
J. C. Tong (2011)
Prodrug and conjugate drug delivery strategies for improving HIV/AIDS therapy.
M. Palombo (2009)
Specific microbicides in the prevention of HIV infection
C. Kelly (2011)
The discovery of antiviral compounds targeting adenovirus and herpes simplex virus : assessment of synthetic compounds and natural products
Mårten Strand (2014)
Discovery and Development of Anti-HBV Agents and Their Resistance
K. Kim (2010)
Immunostimulating RNA Delivered by P1500 PEGylated Cationic Liposomes Limits Influenza Infection in C57Bl/6 Mice
E. Goncharova (2020)
A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413
Masayuki Amano (2016)
Insights into Sulfonated Phthalocyanines; Insights into Anionic Tetraaryl Porphyrins; Irradiation of Cationic Metalloporphyrins Bound to DNA
A. F. Gill (2006)
Attacking pathogens through their hosts
P. Kellam (2006)
Acyclic Nucleosides Bearing a Furanyl Scaffold
V. Nair (2005)
Striking Ability of Adenosine-2′(3′)-deoxy-3′(2′)-triphosphates and Related Analogues to Replace ATP as Phosphate Donor for All Four Human, and the Drosophila Melanogaster, Deoxyribonucleoside Kinases
K. Krawiec (2003)
Human adenoviruses : new bioassays for antiviral screening and CD46 interaction
Emma Andersson (2010)
Potent Synergistic Anti-Human Immunodeficiency Virus (HIV) Effects Using Combinations of the CCR5 Inhibitor Aplaviroc with Other Anti-HIV Drugs
Hirotomo Nakata (2008)
Fighting viruses with antibiotics: an overlooked path
P. Colson (2016)
2′-Deoxy-2′-C-trifluoromethyl β-D-Ribonucleoside Analogues: Synthesis and Antiviral Evaluations
F. Jeannot (2003)
Serge L. Beaucage (2006)
Therapeutic applications of sulfamates
Jean-Yves Winum (2004)
Binding of the Methyl Donor S-Adenosyl-l-Methionine to Middle East Respiratory Syndrome Coronavirus 2′-O-Methyltransferase nsp16 Promotes Recruitment of the Allosteric Activator nsp10
Wahiba Aouadi (2016)
Antiviral drugs: A step ahead of drug resistance
A. Rowan (2005)
Viral and cellular RNA helicases as antiviral targets
A. Kwong (2005)
Identification of Inhibitors for the DEDDh Family of Exonucleases and a Unique Inhibition Mechanism by Crystal Structure Analysis of CRN-4 Bound with 2-Morpholin-4-ylethanesulfonate (MES).
Kuan-Wei Huang (2016)
Schiff Bases: Multipurpose Pharmacophores with Extensive Biological Applications
K. S. Munawar (2018)
The design of drugs for HIV and HCV
E. Clercq (2007)
Antiviral agents active against influenza A viruses
E. Clercq (2006)
HIV-1 Polymerase Inhibition by Nucleoside Analogs: Cellular- and Kinetic Parameters of Efficacy, Susceptibility and Resistance Selection
M. Kleist (2012)
Antiviral Drugs
R. Vardanyan (2016)
Synthesis of Cyclobutane Analogue 4: Preparation of Purine and Pyrimidine Carbocyclic Nucleoside Derivatives
Noha Hasaneen (2019)
Inhibitors of Foot and Mouth Disease Virus Targeting a Novel Pocket of the RNA-Dependent RNA Polymerase
Ryan C. Durk (2010)
Recent highlights in the development of new antiviral drugs
E. De Clercq (2005)
Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication
Y. G. Shin (2020)
Synthesis of a New Scytovirin Protein Derivative, Sd1-Sd2-Sd2, to Decrease Hiv-1 Binding Affinity
A. M. Wood (2013)
See more
Semantic Scholar Logo Some data provided by SemanticScholar