3I06

Crystal structure of cruzain covalently bound to a purine nitrile

Summary for 3I06

• Entry DOI: 10.2210/pdb3i06/pdb
• Descriptor: Cruzipain, 6-[(3,5-difluorophenyl)amino]-9-ethyl-9H-purine-2-carbonitrile (3 entities in total)
• Functional Keywords: autocatalytic cleavage, glycoprotein, protease, thiol protease, zymogen, hydrolase
• Biological source: Trypanosoma cruzi
• Total number of polymer chains: 1
• Total formula weight: 23015.40

Authors

Ferreira, R.S.,Shoichet, B.K.,McKerrow, J.H. (deposition date: 2009-06-24, release date: 2009-12-15, Last modification date: 2024-10-30)

Primary citation

Mott, B.T.,Ferreira, R.S.,Simeonov, A.,Jadhav, A.,Ang, K.K.,Leister, W.,Shen, M.,Silveira, J.T.,Doyle, P.S.,Arkin, M.R.,McKerrow, J.H.,Inglese, J.,Austin, C.P.,Thomas, C.J.,Shoichet, B.K.,Maloney, D.J.
Identification and optimization of inhibitors of trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB.
J.Med.Chem., 53:52-60, 2010

PubMed Abstract: Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas' disease and African sleeping sickness, respectively. Both parasites rely on essential cysteine proteases for survival: cruzain for T. cruzi and TbCatB/rhodesain for T. brucei. A recent quantitative high-throughput screen of cruzain identified triazine nitriles, which are known inhibitors of other cysteine proteases, as reversible inhibitors of the enzyme. Structural modifications detailed herein, including core scaffold modification from triazine to purine, improved the in vitro potency against both cruzain and rhodesain by 350-fold, while also gaining activity against T. brucei parasites. Selected compounds were screened against a panel of human cysteine and serine proteases to determine selectivity, and a cocrystal was obtained of our most potent analogue bound to cruzain.

PubMed: 19908842
DOI: 10.1021/jm901069a

Experimental method

X-RAY DIFFRACTION (1.1 Å)