PT  - JOURNAL ARTICLE
AU  - Mirella Vivoli
AU  - Thomas R. Caulfield
AU  - Karina Martinez-Mayorga
AU  - Alan T. Johnson
AU  - Guan-Sheng Jiao
AU  - Iris Lindberg
TI  - Inhibition of PC1/3 and PC2 by 2,5-Dideoxystreptamine Derivatives
AID  - 10.1124/mol.111.077040
DP  - 2011 Dec 14
TA  - Molecular Pharmacology
PG  - mol.111.077040
4099  - http://molpharm.aspetjournals.org/content/early/2011/12/14/mol.111.077040.short
4100  - http://molpharm.aspetjournals.org/content/early/2011/12/14/mol.111.077040.full
AB  - The prohormone convertases PC1/3 and PC2 are eukaryotic serine proteases involved in the proteolytic maturation of peptide hormone precursors and implicated in a variety of pathological conditions, including obesity, diabetes, and neurodegenerative diseases. In this work, we screened 45 compounds obtained by derivatization of a 2,5-dideoxystreptamine scaffold with guanidinyl and aryl substitutions for convertase inhibition. We identified four promising PC1/3 competitive inhibitors and three PC2 inhibitors which exhibited various inhibition mechanisms (competitive, non-competitive and mixed), with sub- and low micromolar inhibitory potency against a fluorogenic substrate. Low micromolar concentrations of certain compounds blocked the processing of the physiological substrate proglucagon. The best PC2 inhibitor effectively inhibited glucagon synthesis, a known PC2-mediated process, in a pancreatic cell line; no cytotoxicity was observed. We also identified compounds that were able to stimulate both 87 kDa PC1/3 and PC2 activity, behavior related to the presence of aryl groups on the dideoxystreptamine scaffold. By contrast, inhibitory activity was associated with the presence of guanidinyl groups. Molecular modeling revealed interactions of the PC1/3 inhibitors with the active site that suggest structural modifications to further enhance potency. In support of kinetic data suggesting that PC2 inhibition likely occurs via an allosteric mechanism, we identified several possible allosteric binding sites using computational searches. Interestingly, one compound was found to both inhibit PC2 and stimulate PC1/3. Since glucagon acts in functional opposition to insulin in blood glucose homeostasis, blocking glucagon formation and enhancing proinsulin cleavage with a single compound could represent an attractive therapeutic approach in diabetes.