New anti-HIV agents and targets.

Abstract

Virtually all the compounds that are currently used or are subject of advanced clinical trials for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside reverse transcriptase inhibitors (NRTIs): i.e., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine and nucleotide reverse transcriptase inhibitors (NtRTIs) (i.e., tenofovir disoproxil fumarate); (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 (i.e., bicyclam (AMD3100) derivatives) and CCR5 (i.e., TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs, and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e., phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs ( i.e., TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii), as in the case of PIs, a different, modified peptidic (i.e., azapeptidic (atazanavir)) or non-peptidic scaffold (i.e., cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)). Non-peptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs.

• Authors: Erik De Clercq
• Journal: Medicinal research reviews (Med Res Rev) Vol. 22 Issue 6 Pg. 531-65 (Nov 2002) ISSN: 0198-6325 [Print] United States
• PMID: 12369088 (Publication Type: Journal Article, Review)
• Copyright: Copyright 2002 Wiley Periodicals, Inc.

Chemical References

• Anti-HIV Agents
• Capsid Proteins
• Gene Products, gag
• HIV Envelope Protein gp120
• HIV Envelope Protein gp41
• HIV Integrase Inhibitors
• HIV Protease Inhibitors
• NCP7 protein, Human immunodeficiency virus 1
• Receptors, HIV
• Reverse Transcriptase Inhibitors
• Viral Proteins
• gag Gene Products, Human Immunodeficiency Virus
• HIV Reverse Transcriptase
• HIV Protease

Topics

• Amino Acid Sequence
• Anti-HIV Agents (chemistry, pharmacology)
• Binding Sites
• Capsid (drug effects)
• Capsid Proteins
• Drug Resistance, Multiple, Viral
• Gene Products, gag (drug effects)
• HIV Envelope Protein gp120 (drug effects)
• HIV Envelope Protein gp41 (drug effects)
• HIV Integrase Inhibitors (chemistry, pharmacology)
• HIV Protease (drug effects)
• HIV Protease Inhibitors (chemistry, pharmacology)
• HIV Reverse Transcriptase (antagonists & inhibitors, metabolism)
• Humans
• Molecular Sequence Data
• Receptors, HIV (antagonists & inhibitors)
• Reverse Transcriptase Inhibitors (chemistry, pharmacology)
• Transcription, Genetic (drug effects)
• Viral Proteins
• Virus Replication (drug effects)
• gag Gene Products, Human Immunodeficiency Virus