6EXO

Crystal Structure of Rhodesain in complex with a Macrolactam Inhibitor

6EXO の概要

• エントリーDOI: 10.2210/pdb6exo/pdb
• 分子名称: Cysteine protease, 1,2-ETHANEDIOL, (3~{S},14~{E})-19-chloranyl-~{N}-(1-cyanocyclopropyl)-5-oxidanylidene-12,17-dioxa-4-azatricyclo[16.2.2.0^{6,11}]docosa-1(21),6(11),7,9,14,18(22),19-heptaene-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: cysteine protease, papain-like protease, cathepsin l-like protease, endopeptidase, hydrolase
• 由来する生物種: Trypanosoma brucei rhodesiense
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48169.74

構造登録者

Dietzel, U.,Kisker, C. (登録日: 2017-11-08, 公開日: 2018-04-11, 最終更新日: 2024-01-17)

主引用文献

Giroud, M.,Dietzel, U.,Anselm, L.,Banner, D.,Kuglstatter, A.,Benz, J.,Blanc, J.B.,Gaufreteau, D.,Liu, H.,Lin, X.,Stich, A.,Kuhn, B.,Schuler, F.,Kaiser, M.,Brun, R.,Schirmeister, T.,Kisker, C.,Diederich, F.,Haap, W.
Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.
J. Med. Chem., 61:3350-3369, 2018

PubMed Abstract: Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( K < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.

PubMed: 29590750
DOI: 10.1021/acs.jmedchem.7b01869

実験手法

X-RAY DIFFRACTION (1.9 Å)