Positional Scanning Identifies the Molecular Determinants of a High Affinity Multi-Leucine Inhibitor for Furin and PACE4.

The proprotein convertase family of enzymes includes seven endoproteases with significant redundancy in their cleavage activity. We previously described the peptide Ac-LLLLRVK-Amba that displays potent inhibitory effects on both PACE4 and prostate cancer cell lines proliferation. Herein, the molecular determinants for PACE4 and furin inhibition were investigated by positional scanning using peptide libraries that substituted its leucine core with each natural amino acid.

PACE4 inhibitors and their peptidomimetic analogs block prostate cancer tumor progression through quiescence induction, increased apoptosis and impaired neovascularisation.

Prostate cancer is the leading cancer in North American men. Current pharmacological treatments are limited to anti-androgen strategies and the development of new therapeutic approaches remains a challenge. As a fundamentally new approach, we propose the inhibition of PACE4, a member of the proprotein convertases family of enzymes, as a therapeutic target in prostate cancer.

Selective and potent furin inhibitors protect cells from anthrax without significant toxicity.

Furin and related proprotein convertases cleave the multibasic motifs R-X-R/K/X-R in the precursor proteins and, as a result, transform the latent proproteins into biologically active proteins and peptides. Furin is present both in the intracellular secretory pathway and at the cell surface. Intracellular furin processes its multiple normal cellular targets in the Golgi and secretory vesicle compartments while cell-surface furin appears to be essential only for the processing of certain pathogenic proteins and, importantly, anthrax.

New enzyme-activated solubility-switchable contrast agent for magnetic resonance imaging: from synthesis to in vivo imaging.

We designed and synthesized a novel contrast agent (CA) to image the activity of matrix metalloproteinase-2 (MMP-2) in a tumor, noninvasively using magnetic resonance imaging (MRI). We exploited the concept of solubility-switchable CAs in the design of a protease-modulated CA (PCA), referred to as PCA2-switch. This PCA contains a paramagnetic gadolinium chelate (Gd-DOTA), which was attached to the N-terminus of a MMP-2 cleavable peptide sequence via a hydrophobic chain.

Development of an efficient strategy for the synthesis of the ETB receptor antagonist BQ-788 and some related analogues.

BQ-788 [N-cis-2,6-dimethylpiperidine-1-carbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine sodium salt] is a very potent and selective ETB receptor antagonist. The formation of the highly hindered trisubstituted urea functionality in the peptide chain and the carbamination on the indole nitrogen of the tryptophan side chain are major challenges in the synthesis of this particular antagonist. Furthermore, the high cost of the unnatural amino acids in the sequence of BQ-788 and its reported synthesis render this pseudopeptide very expensive to produce.