Structural highlights
Publication Abstract from PubMedBACKGROUND: HIV-1 integrase is a clinically validated therapeutic target for the treatment of HIV-1 infection, with one approved therapeutic currently on the market. This enzyme represents an attractive target for the development of new inhibitors to HIV-1 that are effective against the current resistance mutations. METHODS: A fragment-based screening method employing surface plasmon resonance and NMR was initially used to detect interactions between integrase and fragments. The binding sites of the fragments were elucidated by crystallography and the structural information used to design and synthesize improved ligands. RESULTS: The location of binding of fragments to the catalytic core of integrase was found to be in a previously undescribed binding site, adjacent to the mobile loop. Enzyme assays confirmed that formation of enzyme-fragment complexes inhibits the catalytic activity of integrase and the structural data was utilized to further develop these fragments into more potent novel enzyme inhibitors. CONCLUSIONS: We have defined a new site in integrase as a valid region for the structure-based design of allosteric integrase inhibitors. Using a structure-based design process we have improved the activity of the initial fragments 45-fold. Structural basis for a new mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design.,Rhodes DI, Peat TS, Vandegraaff N, Jeevarajah D, Le G, Jones ED, Smith JA, Coates JA, Winfield LJ, Thienthong N, Newman J, Lucent D, Ryan JH, Savage GP, Francis CL, Deadman JJ Antivir Chem Chemother. 2011 Mar 7;21(4):155-68. PMID:21602613[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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