6EXO

Crystal Structure of Rhodesain in complex with a Macrolactam Inhibitor

Summary for 6EXO

• Entry DOI: 10.2210/pdb6exo/pdb
• Descriptor: 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)
• Functional Keywords: cysteine protease, papain-like protease, cathepsin l-like protease, endopeptidase, hydrolase
• Biological source: Trypanosoma brucei rhodesiense
• Total number of polymer chains: 2
• Total formula weight: 48169.74

Authors

Dietzel, U.,Kisker, C. (deposition date: 2017-11-08, release date: 2018-04-11, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.9 Å)