Proteases and their inhibitors: today and tomorrow.
A major incentive in inhibitor research is that control of limited proteolysis constitutes a valuable pharmacological tool. Protease inhibitors have proved to be successful in influencing pathogenesis in many experimental models but a breakthrough to use in human therapy has mainly been restricted to aprotinin and angiotensin converting enzyme (ACE) inhibitors. However, the success of ACE inhibitors as pharmacological tools in hypertension has proved to be a strong stimulant for new protease inhibitor approaches to drug therapy. While emphasis in the search for next generations of ACE inhibitors may move from the circulation renin-angiotensin system to the local tissue systems, including heart, brain and genital tract, persistent and insightful design of renin inhibitors has already yielded highly specific molecules with potent activities in several in vivo models. The development of orally effective long-acting inhibitors will finally allow an evaluation to be made of their therapeutic profile with regard to the family of ACE inhibitors. The close relationship between renin and HIV-1 protease presents an exceptional opportunity for transfer of the knowledge acquired in renin inhibitor development during the past decade, to an accelerated generation of specific HIV-1 protease inhibitors as effective agents in treatment of AIDS. The self-assembly of 2 identical monomers into a symmetrical structure in HIV-1 protease is not only an elegant way to create an active enzyme while encoding a minimal amount of genetic information, but is also in concordance with the bilobular active-site found in mammalian aspartic proteases.(ABSTRACT TRUNCATED AT 250 WORDS)
Scharpe
S
S
Department of Clinical Biochemistry, University of Antwerp, UIA, Belgium.
De Meester
I
I
Hendriks
D
D
Vanhoof
G
G
van Sande
M
M
Vriend
G
G
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D010450:Endopeptidases / Q000378:metabolism*; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors; D006493:Heparin / Q000378:metabolism; D006629:Hirudins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010875:Pipecolic Acids / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012083:Renin / Q000378:metabolism; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D000092502:Renin Inhibitors
D000806:Angiotensin-Converting Enzyme Inhibitors; D001120:Arginine; D010450:Endopeptidases; D016333:HIV Protease; D017320:HIV Protease Inhibitors; D006493:Heparin; D006629:Hirudins; D007703:Peptidyl-Dipeptidase A; D010875:Pipecolic Acids; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D012083:Renin; D013449:Sulfonamides; D013917:Thrombin; D000092502:Renin Inhibitors; C031942:argatroban