Problems and perspectives in the design of anti‐HIV‐1 agents

The human immunodeficiency virus (HIV) that produces the acquired immune deficiency syndrome (AIDS) continues to evade all strategies for potential therapeutic intervention. Global efforts in the search for potential anti‐HIV‐1 agents have mainly centered around the design of enzyme inhibitors and derivatives that inhibit viral binding or gene expression. Both nucleoside and non‐nucleoside reverse transcriptase inhibitors have demonstrated potent anti‐HIV‐1 activity. However, toxicity considerations and the emergence of resistant strains will require further structural manipulations to diminish these undesirable properties. Protease inhibitors also exhibit activities at nanomolar concentrations, but many of these agents may suffer from problems of absorption and biodegradation. These apparent shortcomings have been circumvented by the preparation of peptidomimetic molecules. Similarly, smaller CD4 mimetics have emerged as alternatives to the larger soluble CD4 derivatives as inhibitors of viral binding. Other viral binding inhibitors, the anionic molecules, suffer from an inherent inability to enter cells and potential anticoagulant activity. These properties may be remedied by rational analog design and synthesis. Oligonucleotides can be constructed to inhibit specific segments of selected regulatory genes of the virus. These agents have been critiqued on the basis of stability, cellular uptake, and assurance of hybridization. Once again, structure activity relationship studies have revealed that many of these apparent problems can be overcome. The more recently discovered agents belong to the unique classes of tat antagonists or viral uncoating inhibitors. © 1993 Wiley‐Liss, Inc. © 1993 Wiley‐Liss, Inc.