5ta2

Discovery of a Potent Cyclophilin Inhibitor (Compound 7) based on Structural Simplification of Sanglifehrin A

spinqualitylabelsall models 5ta2, resolution 1.48Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ta2 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 78X Related: 5t9u, 5t9w, 5t9z, 5ta4 Activity: Peptidylprolyl isomerase, with EC number 5.2.1.8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [PPIA_HUMAN] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Publication Abstract from PubMed Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a pi-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold, to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors. Discovery of Potent Cyclophilin Inhibitors based on Structural Simplification of Sanglifehrin A.,Steadman VA, Pettit SB, Poullennec KG, Lazarides L, Keats AJ, Dean DK, Stanway SJ, Austin CA, Sanvoisin JA, Watt GM, Fliri HG, Liclican AC, Jin D, Wong MH, Leavitt SA, Lee YJ, Tian Y, Frey CR, Appleby TC, Schmitz U, Jansa P, Mackman RL, Schultz BE J Med Chem. 2017 Jan 11. doi: 10.1021/acs.jmedchem.6b01329. PMID:28075591 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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