Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends

J Med Chem. 2016 Apr 14;59(7):2849-78. doi: 10.1021/acs.jmedchem.5b00497. Epub 2015 Nov 5.

Abstract

The early effectiveness of combinatorial antiretroviral therapy (cART) in the treatment of HIV infection has been compromised to some extent by rapid development of multidrug-resistant HIV strains, poor bioavailability, and cumulative toxicities, and so there is a need for alternative strategies of antiretroviral drug discovery and additional therapeutic agents with novel action modes or targets. From this perspective, we first review current strategies of antiretroviral drug discovery and optimization, with the aid of selected examples from the recent literature. We highlight the development of phosphate ester-based prodrugs as a means to improve the aqueous solubility of HIV inhibitors, and the introduction of the substrate envelope hypothesis as a new approach for overcoming HIV drug resistance. Finally, we discuss future directions for research, including opportunities for exploitation of novel antiretroviral targets, and the strategy of activation of latent HIV reservoirs as a means to eradicate the virus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology*
  • Chemistry, Pharmaceutical / methods*
  • Chemistry, Pharmaceutical / trends
  • Chemoprevention / methods
  • Drug Design
  • Drug Discovery
  • Drug Resistance, Viral / drug effects
  • Drug Resistance, Viral / genetics
  • HIV Protease Inhibitors / pharmacology
  • Humans
  • Molecular Targeted Therapy / methods
  • Mutation
  • Prodrugs / chemistry
  • Solubility
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • HIV Protease Inhibitors
  • Prodrugs