Protein farnesyl and N-myristoyl transferases: piggy-back medicinal chemistry targets for the development of antitrypanosomatid and antimalarial therapeutics.
To accelerate progress in the development of therapeutics for protozoan parasitic diseases, we are studying enzymes active in co- and post-translational protein modification that are already the focus of drug development in other eukaryotic systems. Inhibitors of the protein farnesyltransferases (PFT) are well-established antitumour agents of low cytotoxicity and known pharmokinetic properties, while inhibitors of N-myristoyl transferase show both selectivity and specificity in the treatment of fungal infections. Here, we summarise the current evidence that supports the targeting of these ubiquitous eukaryotic enzymes for drug development against trypanosomatid infections and malaria.
Gelb
Michael H
MH
Department of Chemistry, University of Washington, Seattle, WA 98195, USA. gelb@chem.washington.edu
Van Voorhis
Wesley C
WC
Buckner
Frederick S
FS
Yokoyama
Kohei
K
Eastman
Richard
R
Carpenter
Elisabeth P
EP
Panethymitaki
Chrysoula
C
Brown
Katherine A
KA
Smith
Deborah F
DF
D000217:Acyltransferases / Q000737:chemistry; D019883:Alkyl and Aryl Transferases / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis*; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D010961:Plasmodium / Q000201:enzymology; D011487:Protein Conformation; D014344:Trypanocidal Agents / Q000138:chemical synthesis*; D014345:Trypanosoma / Q000201:enzymology
D000962:Antimalarials; D014344:Trypanocidal Agents; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase