Authors: Fugere, M.; Day, R.

Source: Current Pharmaceutical Design, Volume 8, Number 7, 1 March 2002 , pp. 549-562(14)

Publisher: Bentham Science Publishers

Abstract:

Following protein biosynthesis, some of the most important cellular mechanisms that generate biological diversity are the enzymatically driven post-translational modifications that ultimately lead to the formation of bioactive molecules. Within the secretory pathway, a multitude of precursor proteins are thus modified resulting in hormones, neuropeptides, growth factors, receptors and even enzymes. These modifications include cleavage at specific sites through endo- or exo-peptidase action, amidation, glycosylation and sulfation. In recent years, an important family of these processing enzymes was discovered and characterized. The so-called proprotein convertases are the products of seven distinct genes and function as endopeptidases that cleave protein precursors C-terminal to basic residue sites. They are structurally related to the bacterial subtilisin family of enzymes and are thus referred to as the subtilisin-like proprotein convertases (SPCs). Many studies have examined the inhibition of this family of enzymes, through the search of endogenous inhibitors or through the development of peptidyl, non-peptidyl or protein inhibitors. Some potent inhibitors have been discovered or engineered. While it is certain that potent inhibitors could serve as important tools to further elucidate the specific functions of each SPC, it has also been suggested that such inhibitors may be developed into lead compounds that could have important therapeutic applications. This review examines the progress made in regards to endogenous and engineered inhibitors and evidence for possible uses as molecular tools or in therapeutic applications. It is noted that although important inhibitory potencies have often been reported, there is generally insufficient evidence to demonstrate high levels of specificity. It is thus suggested that an important short-term challenge before the field will be a better understanding of the catalytic specificity of each SPC.

Keywords: subtilase-like pro-protein convertases(spcs); convertase; inhibitors; serine proteinases; at-pax; endogenous inhibitors; prosaas; prodomains; peptidyl inhibitors; bioengineered inhibitors

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1381612023395736

Publication date: 2002-03-01

More about this publication?

• Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
  
  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

Related content

• In this: publication
• By this: publisher
• In this Subject: Pharmacology
• By this author: Fugere, M. ;  Day, R.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers