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A comparative protease stability study of synthetic macrocyclic peptides that mimic two endocrine hormones.

Abstract：

:Peptide therapeutics have traditionally faced many challenges including low bioavailability, poor proteolytic stability and difficult cellular uptake. Conformationally constraining the backbone of a peptide into a macrocyclic ring often ameliorates these problems and allows for the development of a variety of new drugs. Such peptide-based pharmaceuticals can enhance the multi-faceted functionality of peptide side chains, permitting the peptides to bind cellular targets and receptors necessary to impart their role, while protecting them from degrading cellular influences. In the work described here, we developed three cyclic peptides, VP mimic1, VP mimic2 and OT mimic1, which mimic endocrine hormones vasopressin and oxytocin. Making notable changes to the overall structure and composition of the parent hormones, we synthesized the mimics and tested their durability against treatment with three proteases chosen for their specificity: pepsin, alpha-chymotrypsin, and pronase. Vasopressin and oxytocin contain a disulfide linkage leaving them particularly vulnerable to deactivation from the reducing environment inside the cell. Thus, we increased the complexity of our assays by adding reducing agent glutathione to each mixture. Subsequently, we discovered each of our mimics withstood protease treatment with less degradation and/or a slower rate of degradation as compared to both parent hormones and a linear control peptide.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Ferrie JJ,Gruskos JJ,Goldwaser AL,Decker ME,Guarracino DA

doi

10.1016/j.bmcl.2012.12.041

subject

Has Abstract

pub_date

2013-02-15 00:00:00

pages

989-95

issue

4

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(12)01635-6

journal_volume

23

pub_type

杂志文章

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