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Multibranch and Pseudopeptide Approach for Design of Novel Inhibitors of Subtilisin Kexin Isozyme-1

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Here we developed small molecule inhibitors of SKI-1/S1P enzyme of the Proprotein Convertase family following two approaches. One involves the assembly of multi-branch peptides while the other utilizes the insertion of alkyloxy pseudo peptide bond at P1-P1' cleavage position. In first approach, 2 and 4-branch peptides were designed based on the human (h) SKI-1128-137 sequence, located N-terminal to its secondary activation site (K137fl⇓ L). The 4-branch peptide exhibited the highest SKI-1 inhibitory property (IC50 = 0.9 μM) with ∼8.6 and 1.3-fold more potency than the corresponding single and 2-branch peptides, respectively. In the second strategy, an oxymethylene containing unnatural amino acid such as aminooxy-acetic acid (Aoaa) or 8-amino-3, 6 dioxa-octanoic acid (Adoa) was introduced substituting P1, P1' or both residues of hSKI-1183-190 and hSKI-1178-190 segments. These domains contain the same primary hSKI-1 activation site L186 R. Among those tested, P7-Tyr mutant [178GRYSSRRL(Adoa)AIP190] exhibited higher SKI-1 inhibitory activity (Ki in low μM). Circular dichroism (CD) spectra of SKI-1 inhibitors showed interactions of varying degrees between the enzyme and the inhibitor consistent with the observed inhibition profile. A 3D-homology model structure of SKI-1 catalytic domain indicated a broad catalytic pocket.

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Keywords: Circular dichroism; Enzyme inhibitors; Inhibition constant; Isostere; Mass spectrometry; Multibranch peptide; Pseudopeptide; Secondary structure; Site 1 Protease (S1P); Subtilisin Kexin Isozyme-1 (SKI-1)

Document Type: Research Article

Affiliations: Regional Protein Chemistry Center, Diseases of Aging Program, Ottawa Health Research Institute, 725 Parkdale Ave, Ottawa, ON. K1Y 4E9, Canada.

Publication date: 2006-09-01

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  • Protein & Peptide Letters publishes short papers in all important aspects of protein and peptide research, including structural studies, recombinant expression, function, synthesis, enzymology, immunology, molecular modeling, drug design etc. Manuscripts must have a significant element of novelty, timeliness and urgency that merit rapid publication. Reports of crystallisation, and preliminary structure determinations of biologically important proteins are acceptable. Purely theoretical papers are also acceptable provided they provide new insight into the principles of protein/peptide structure and function.
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