3aid
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(New page: 200px<br /> <applet load="3aid" size="450" color="white" frame="true" align="right" spinBox="true" caption="3aid, resolution 2.5Å" /> '''A NEW CLASS OF HIV-1...)
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Revision as of 12:52, 8 November 2007
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A NEW CLASS OF HIV-1 PROTEASE INHIBITOR: THE CRYSTALLOGRAPHIC STRUCTURE, INHIBITION AND CHEMICAL SYNTHESIS OF AN AMINIMIDE PEPTIDE ISOSTERE
Overview
The essential role of HIV-1 protease (HIV-1 PR) in the viral life cycle, makes it an attractive target for the development of substrate-based, inhibitors that may find efficacy as anti-AIDS drugs. However, resistance, has arisen to potent peptidomimetic drugs necessitating the further, development of novel chemical backbones for diversity based chemistry, focused on probing the active site for inhibitor interactions and binding, modes that evade protease resistance. AQ148 is a potent inhibitor of HIV-1, PR and represents a new class of transition state analogues incorporating, an aminimide peptide isostere. A 3-D crystallographic structure of AQ148, a tetrapeptide isostere, has been determined in complex with its target, HIV-1 PR to a resolution of 2.5 A and used to evaluate the specific, structural determinants of AQ148 potency and to correlate, structure-activity relationships within the class of related compounds., AQ148 is a competitive inhibitor of HIV-1 PR with a Ki value of 137 nM., Twenty-nine derivatives have been synthesized and chemical modifications, have been made at the P1, P2, P1', and P2' sites. The atomic resolution, structure of AQ148 bound to HIV-1 PR reveals both an inhibitor binding, mode that closely resembles that of other peptidomimetic inhibitors and, specific protein/inhibitor interactions that correlate with, structure-activity relationships. The structure provides the basis for the, design, synthesis and evaluation of the next generation of hydroxyethyl, aminimide inhibitors. The aminimide peptide isostere is a scaffold with, favorable biological properties well suited to both the combinatorial, methods of peptidomimesis and the rational design of potent and specific, substrate-based analogues.
About this Structure
3AID is a Single protein structure of sequence from Human immunodeficiency virus with ARQ as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
Reference
A new class of HIV-1 protease inhibitor: the crystallographic structure, inhibition and chemical synthesis of an aminimide peptide isostere., Rutenber EE, McPhee F, Kaplan AP, Gallion SL, Hogan JC Jr, Craik CS, Stroud RM, Bioorg Med Chem. 1996 Sep;4(9):1545-58. PMID:8894111
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