New anti-HIV agents and targets

Med Res Rev. 2002 Nov;22(6):531-65. doi: 10.1002/med.10021.

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.

Publication types

  • Review

MeSH terms

  • Amino Acid Sequence
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / 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
  • HIV Integrase Inhibitors / pharmacology
  • HIV Protease / drug effects*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • Humans
  • Molecular Sequence Data
  • Receptors, HIV / antagonists & inhibitors*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Transcription, Genetic / drug effects
  • Viral Proteins*
  • Virus Replication / drug effects*
  • gag Gene Products, Human Immunodeficiency Virus

Substances

  • 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