5TA2

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

Summary for 5TA2

• Entry DOI: 10.2210/pdb5ta2/pdb
• Related: 5T9U 5T9W 5T9Z 5TA4
• Related PRD ID: PRD_002246
• Descriptor: Peptidyl-prolyl cis-trans isomerase A, 11-[(3-hydroxyphenyl)methyl]-18-methoxy-2,17-dimethyl-14-(propan-2-yl)-3-oxa-9,12,15,28-tetraazatricyclo[21.3.1.1~5,9~]octacosa-1(27),21,23,25-tetraene-4,10,13,16-tetrone (3 entities in total)
• Functional Keywords: cyclophilin inhibitor antiviral hcv, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P62937
• Total number of polymer chains: 1
• Total formula weight: 18424.98

Authors

Appleby, T.C.,Steadman, V.,Pettit, S.,Schmitz, U.,Mackman, R.L.,Schultz, B. (deposition date: 2016-09-09, release date: 2017-01-25, Last modification date: 2024-03-06)

Primary citation

Steadman, V.A.,Pettit, S.B.,Poullennec, K.G.,Lazarides, L.,Keats, A.J.,Dean, D.K.,Stanway, S.J.,Austin, C.A.,Sanvoisin, J.A.,Watt, G.M.,Fliri, H.G.,Liclican, A.C.,Jin, D.,Wong, M.H.,Leavitt, S.A.,Lee, Y.J.,Tian, Y.,Frey, C.R.,Appleby, T.C.,Schmitz, U.,Jansa, P.,Mackman, R.L.,Schultz, B.E.
Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A.
J. Med. Chem., 60:1000-1017, 2017

PubMed Abstract: 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 π-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.

PubMed: 28075591
DOI: 10.1021/acs.jmedchem.6b01329

Experimental method

X-RAY DIFFRACTION (1.48 Å)