Inhibition of prohormone convertases PC1/3 and PC2 by 2,5- dideoxystreptamine derivatives

Mirella Vivoli, Thomas Caulfield, Karina Martínez-Mayorga, Alan T. Johnson, Guan Sheng Jiao, Iris Lindberg

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The prohormone convertases PC1/3 and PC2 are eukaryotic serine proteases involved in the proteolytic maturation of peptide hormone precursors and are 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 that exhibited various inhibition mechanisms (competitive, noncompetitive, 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 probably occurs via an allosteric mechanism, we identified several possible allosteric binding sites using computational searches. It is noteworthy that one compound was found to both inhibit PC2 and stimulate PC1/3. Because 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.

Original languageEnglish (US)
Pages (from-to)440-454
Number of pages15
JournalMolecular Pharmacology
Volume81
Issue number3
DOIs
StatePublished - Mar 2012
Externally publishedYes

Fingerprint

Proprotein Convertase 2
Proprotein Convertase 1
Glucagon
Proglucagon
Allosteric Site
Proinsulin
Peptide Hormones
Serine Proteases
Fluorescent Dyes
Neurodegenerative Diseases
Blood Glucose
Catalytic Domain
Homeostasis
Obesity
Binding Sites
Insulin
Cell Line
2,5-dideoxystreptamine
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Pharmacology

Cite this

Inhibition of prohormone convertases PC1/3 and PC2 by 2,5- dideoxystreptamine derivatives. / Vivoli, Mirella; Caulfield, Thomas; Martínez-Mayorga, Karina; Johnson, Alan T.; Jiao, Guan Sheng; Lindberg, Iris.

In: Molecular Pharmacology, Vol. 81, No. 3, 03.2012, p. 440-454.

Research output: Contribution to journalArticle

Vivoli, M, Caulfield, T, Martínez-Mayorga, K, Johnson, AT, Jiao, GS & Lindberg, I 2012, 'Inhibition of prohormone convertases PC1/3 and PC2 by 2,5- dideoxystreptamine derivatives', Molecular Pharmacology, vol. 81, no. 3, pp. 440-454. https://doi.org/10.1124/mol.111.077040
Vivoli, Mirella ; Caulfield, Thomas ; Martínez-Mayorga, Karina ; Johnson, Alan T. ; Jiao, Guan Sheng ; Lindberg, Iris. / Inhibition of prohormone convertases PC1/3 and PC2 by 2,5- dideoxystreptamine derivatives. In: Molecular Pharmacology. 2012 ; Vol. 81, No. 3. pp. 440-454.
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