Pharmacology Research Today is a free monthly online journal that collates and summarizes the latest research about Pharmacology, including details on pharmacogenomics, drug development, new medications.

Efficient degradation-aided selection of protease inhibitors by phage display.

Hawinkels LJ, van Rossenberg SM, de Jonge-Muller ES, Molenaar TJ, Appeldoorn CC, van Berkel TJ, Sier CF, Biessen EA

Leiden/Amsterdam Centre for Drug Research, Division of Biopharmaceutics, Leiden, The Netherlands. L.J.A.C.Hawinkels@LUMC.nl

In this report, we describe a novel phage display strategy for the identification of dedicated protease inhibiting peptides, based on degradation-aided enrichment of protease resistant phages. Phages were directly incubated with a range of phage-degrading proteases, after which non-degraded phages were used for the next selection round. For proteinase-K we identified after only four selection rounds a peptide (VLIMPVLLGIPLLC) that inhibits proteinase-K activity with an inhibition constant of 4 microM. In analogy, we identified a peptide capable of inhibiting substrate degradation by cathepsin-S (VWNCERITISRLIN), which showed functional inhibition of cathepsin-S induced sprouting of endothelial cells. We envision that the pursued strategy of degradation-aided selection of protease inhibitors (DASPI) represents an effective approach in the design of new protease inhibitors but also of new strategies to render gene and drug vectors protease resistant.

Published 7 November 2007 in Biochem Biophys Res Commun, 364(3): 549-55.
Full-text of this article is available online (may require subscription).

© 2005-2008 Pharmacology Research Today. All Rights Reserved.