Evaluation of NAD(H) analogues as selective inhibitors for Trypanosoma cruzi S-adenosylhomocysteine hydrolase.
S-Adenosylhomocysteine (AdoHcy) hydrolases (SAHHs) from human sources (Hs-SAHHs) bind the cofactor NAD(+) more tightly than several parasitic SAHHs by around 1000-fold. This property suggests the cofactor binding site of this essential enzyme as a potential anti-parasitic drug target, e.g., against SAHH from Trypansoma cruzi (Tc-SAHH). The on-rate and off-rate constants and the equilibrium dissociation constants were determined for NAD(+)/NADH analogues and suggested that NADH analogues were the most promising for selective inhibition of Tc-SAHH. None significantly inhibited Hs-SAHH while S-NADH and H-NADH (see Figure 1) reduced the catalytic activity of Tc-SAHH to < 10% in six minutes of exposure.
Li
Qing-Shan
QS
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, USA.
Cai
Sumin
S
Fang
Jianwen
J
Borchardt
Ronald T
RT
Kuczera
Krzysztof
K
Middaugh
C Russell
CR
Schowen
Richard L
RL
D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014355:Chagas Disease / Q000188:drug therapy; D006801:Humans; D009243:NAD / Q000031:analogs & derivatives*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
D014344:Trypanocidal Agents; D009243:NAD; D043383:Adenosylhomocysteinase