Peptidomimetic inhibitors of HIV protease.
There are currently (July, 2002) six protease inhibitors approved for the treatment of HIV infection, each of which can be classified as peptidomimetic in structure. These agents, when used in combination with other antiretroviral agents, produce a sustained decrease in viral load, often to levels below the limits of quantifiable detection, and a significant reconstitution of the immune system. Therapeutic regimens containing one or more HIV protease inhibitors thus provide a highly effective method for disease management. The important role of protease inhibitors in HIV therapy, combined with numerous challenges remaining in HIV treatment, have resulted in a continued effort both to optimize regimens using the existing agents and to identify new protease inhibitors that may provide unique properties. This review will provide an overview of the discovery and clinical trials of the currently approved HIV protease inhibitors, followed by an examination of important aspects of therapy, such as pharmacokinetic enhancement, resistance and side effects. A description of new peptidomimetic compounds currently being investigated in the clinic and in preclinical discovery will follow.
Randolph
John T
JT
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois, USA. john.randolph@abbott.com
DeGoey
David A
DA
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000069446:Atazanavir Sulfate; D002219:Carbamates; D002986:Clinical Trials as Topic; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D005663:Furans; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology / Q000627:therapeutic use; D061466:Lopinavir; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D019888:Nelfinavir / Q000494:pharmacology / Q000627:therapeutic use; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019438:Ritonavir / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019258:Saquinavir / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014520:Urethane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D019380:Anti-HIV Agents; D002219:Carbamates; C444448:DPC 681; D004151:Dipeptides; D005663:Furans; D017320:HIV Protease Inhibitors; C120671:JE 2147; D009842:Oligopeptides; D010755:Organophosphates; D010455:Peptides; D010654:Phenylbutyrates; D011725:Pyridines; D011744:Pyrimidinones; D013449:Sulfonamides; C446340:UIC-94003; D061466:Lopinavir; D014520:Urethane; D000069446:Atazanavir Sulfate; C095108:amprenavir; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir; C426859:fosamprenavir