Nmr Structural And Dynamics Studies Of Hiv-1 Protease

Dental & Craniofacial Research

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Abstract

The mature, active HIV-1 protease is a homodimer that is made up of monomer subunits containing 99 amino acid residues. At least eight FDA-approved anti-protease drugs have been developed. Each of these drugs binds tightly to the dimer active site, thereby inhibiting catalytic activity and preventing propagation of the AIDs virus; however, one unfortunate consequence of targeting a single site on the protease has been the emergence of viral strains which carry multi-drug resistant mutations within their protease molecules. For this reason, there is considerable interest in identifying alternative protease sites that are suitable drug targets. Of particular interest are compounds that bind to the interface of the dimer. Such compounds will block formation of the active protease dimer, but be insensitive to current multidrug-resistant protease variants. In spite of these attractive features, dimerizatioin inhibitors face the formidable challenge of dissociating the tightly bound mature protease homodimer. As noted in previous reports, we have shown that, in contrast with the mature protease, protease constructs, among them those that contain N-terminal extensions (similar to those of the protease precursor, which is embedded within the Gag-Pol polyprotein), have million-fold larger dissociation constants, and are predominantly monomeric at concentrations required for NMR studies. These discoveries suggest that the precursor monomer, rather than the mature protease monomer, is the target of choice of dimerization inhibitors. This work had been carried out by Dr. Rieko Ishima (NIDCR) under the supervision of Dr. Torchia and in collaboration with Dr. John Louis (NIDDK). In November of 2005 Dr. Ishima became a tenure track investigator at the Univ. of Pittsburgh Medical School, where she is establishing a program to discover molecules that interact with models of protease precursor monomer constructs, in order to identify inhibitors of precursor dimerization. As a consequence of her departure and the retirement of Dr. Dennis Torchia in the Spring of 2006, this MSBU program is no longer active.