Aspartic peptidase inhibitors: implications in drug development.
The last decade has witnessed an effervescence of research interest in the development of potent inhibitors of various aspartic peptidases. As an enzyme family, aspartic peptidases are relatively a small group that has received enormous interest because of their significant roles in human diseases like involvement of renin in hypertension, cathepsin D in metastasis of breast cancer, beta-Secretase in Alzheimer's Disease, plasmepsins in malaria, HIV-1 peptidase in acquired immune deficiency syndrome, and secreted aspartic peptidases in candidal infections. There have been developments on clinically active inhibitors of HIV-1 peptidase, which have been licensed for the treatment of AIDS. The inhibitors of plasmepsins and renin are considered a viable therapeutic strategy for the treatment of malaria and hypertension. Relatively few inhibitors of cathepsin D have been reported, partly because of its uncertain role as a viable target for therapeutic intervention. The beta-secretase inhibitors OM99-2 and OM003 were designed based on the substrate specificity information. The present article is a comprehensive state-of-the-art review describing the aspartic peptidase inhibitors illustrating the recent developments in the area. In addition, the homologies between the reported inhibitor sequences have been analyzed. The understanding of the structure-function relationships of aspartic peptidases and inhibitors will have a direct impact on the design of new inhibitor drugs.
Division of Biochemical Sciences, National Chemical Laboratory, Pune 411008, India.
Chandravanu
C
Dash
Aarohi
A
Kulkarni
Ben
B
Dunn
Mala
M
Rao
D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism*; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010447:Peptide Hydrolases / Q000145:classification; D011480:Protease Inhibitors / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D017385:Sequence Homology; D000092502:Renin Inhibitors
D016282:Aspartic Acid Endopeptidases; D017320:HIV Protease Inhibitors; D010447:Peptide Hydrolases; D011480:Protease Inhibitors; D000092502:Renin Inhibitors