The Rationale for Targeting the NAD/NADH Cofactor Binding Site of Parasitic S-Adenosyl-L-Homocysteine Hydrolase for the Design of Anti-Parasitic Drugs

• Published in: Nucleosides, nucleotides & nucleic acids Vol. 28; no. 5-7; pp. 485 - 503
• Main Authors: Cai, Sumin, Li, Qing-Shan, Fang, Jianwen, Borchardt, Ronald T., Kuczera, Krzysztof, Middaugh, C. Russell, Schowen, Richard L.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis Group 01.05.2009
• Subjects: Adenosylhomocysteinase - antagonists & inhibitors; Adenosylhomocysteinase - chemistry; Adenosylhomocysteinase - metabolism; anti-parasitic drugs; Binding Sites; Chagas Disease - drug therapy; cofactor-site targeting; enzyme inhibitors; Humans; Models, Molecular; NAD - chemistry; NAD - metabolism; Protein Binding; Protein Conformation; S-adenosylhomocysteine; Substrate Specificity; Thermodynamics; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi - enzymology
• ISSN: 1525-7770; 1532-2335
• DOI: 10.1080/15257770903051031

Trypanosomal S-adenoyl-L-homocysteine hydrolase (Tc-SAHH), considered as a target for treatment of Chagas disease, has the same catalytic mechanism as human SAHH (Hs-SAHH) and both enzymes have very similar x-ray structures. Efforts toward the design of selective inhibitors against Tc-SAHH targeting the substrate binding site have not to date shown any significant promise. Systematic kinetic and thermodynamic studies on association and dissociation of cofactor NAD/H for Tc-SAHH and Hs-SAHH provide a rationale for the design of anti-parasitic drugs directed toward cofactor-binding sites. Analogues of NAD and their reduced forms show significant selective inactivation of Tc-SAHH, confirming that this design approach is rational.