Design and characterization of an HIV-specific ribonuclease zymogen.
Ribonucleases are evoking medical interest because of their intrinsic cytotoxic activity. Most notably, ranpirnase, which is an amphibian ribonuclease, is in advanced clinical trials as a chemotherapeutic agent for the treatment of cancer. Here, we describe a strategy to create a novel antiviral agent based on bovine pancreatic ribonuclease (RNase A), a mammalian homologue of ranpirnase. Specifically, we have linked the N- and C-termini of RNase A with an amino acid sequence that is recognized and cleaved by human immunodeficiency virus (HIV) protease. This linkage obstructs the active site, forming an HIV-specific RNase A zymogen. Cleavage by HIV-1 protease increases ribonucleolytic activity by 50-fold. By relying on the proper function of HIV-1 protease, rather than its inhibition, our approach will not engender known mechanisms of resistance. Thus, we report an initial step toward a new class of agents for the treatment of HIV/AIDS.
Turcotte
Rebecca F
RF
Medical Scientist Training Program and Biophysics Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
Raines
Ronald T
RT
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D015195:Drug Design; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020014:K562 Cells; D012259:Ribonuclease, Pancreatic / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D012260:Ribonucleases / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D013379:Substrate Specificity
D019380:Anti-HIV Agents; D004792:Enzyme Precursors; D012260:Ribonucleases; D012259:Ribonuclease, Pancreatic; C058703:ranpirnase