HIV protease as a target for retrovirus vector-mediated gene therapy.
The dimeric aspartyl protease of HIV has been the subject of intense research for almost a decade. Knowledge of the substrate specificity and catalytic mechanism of this enzyme initially guided the development of several potent peptidomimetic small molecule inhibitors. More recently, the solution of the HIV protease structure led to the structure-based design of improved peptidomimetic and non-peptidomimetic antiviral compounds. Despite the qualified success of these inhibitors, the high mutation rate associated with RNA viruses continues to hamper the long-term clinical efficacy of HIV protease inhibitors. The dimeric nature of the viral protease has been conducive to the investigation of dominant-negative inhibitors of the enzyme. Some of these inhibitors are defective protease monomers that interact with functional monomers to form inactive protease heterodimers. An advantage of macromolecular inhibitors as compared to small-molecule inhibitors is the increased surface area of interaction between the inhibitor and the target gene product. Point mutations that preserve enzyme activity but confer resistance to small-molecule inhibitors are less likely to have an adverse effect on macromolecular interactions. The use of efficient retrovirus vectors has facilitated the delivery of these macromolecular inhibitors to primary human lymphocytes. The vector-transduced cells were less susceptible to HIV infection in vitro, and showed similar levels of protection compared to other macromolecular inhibitors of HIV replication, such as RevM10. These preliminary results encourage the further development of dominant-negative HIV protease inhibitors as a gene therapy-based antiviral strategy.
Todd
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Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143-0446, USA. todd@cgl.ucsf.edu
Anderson
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Jolly
D J
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Craik
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D000595:Amino Acid Sequence; D002219:Carbamates; D005663:Furans; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D019469:Indinavir / Q000737:chemistry; D016086:Lentivirus / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D019888:Nelfinavir / Q000737:chemistry; D012190:Retroviridae / Q000235:genetics*; D019438:Ritonavir / Q000737:chemistry; D019258:Saquinavir / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry; D014162:Transfection
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D019469:Indinavir; D016333:HIV Protease; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir