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J Med Chem. 2017 May 11;60(9):3814-3827. doi: 10.1021/acs.jmedchem.7b00018. Epub 2017 Apr 19.

Second Generation Triple-Helical Peptide Inhibitors of Matrix Metalloproteinases.

Author information

1
Torrey Pines Institute for Molecular Studies , 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
2
Sigma-Aldrich Corporation , 3 Strathmore Road, Natick, Massachusetts 01760, United States.
3
Florida Atlantic University , 5353 Parkside Drive, Jupiter, Florida 33458, United States.
4
Cincinnati Children's Hospital Medical Center , 3333 Burnet Avenue, Cincinnati, Ohio 45229, United States.
5
University of Texas Health Science Center , 7703 Floyd Curl Drive, San Antonio Texas 78229, United States.
6
The Scripps Research Institute/Scripps Florida , 130 Scripps Way, Jupiter, Florida 33458, United States.
7
School of Dental Medicine, Tufts University , 1 Kneeland Street, Boston, Massachusetts 02111, United States.

Abstract

The design of selective matrix metalloproteinase (MMP) inhibitors that also possess favorable solubility properties has proved to be especially challenging. A prior approach using collagen-model templates combined with transition state analogs produced a first generation of triple-helical peptide inhibitors (THPIs) that were effective in vitro against discrete members of the MMP family. These THPI constructs were also highly water-soluble. The present study sought improvements in the first generation THPIs by enhancing thermal stability and selectivity. A THPI selective for MMP-2 and MMP-9 was redesigned to incorporate non-native amino acids (Flp and mep), resulting in an increase of 18 °C in thermal stability. This THPI was effective in vivo in a mouse model of multiple sclerosis, reducing clinical severity and weight loss. Two other THPIs were developed to be more selective within the collagenolytic members of the MMP family. One of these THPIs was serendipitously more effective against MMP-8 than MT1-MMP and was utilized successfully in a mouse model of sepsis. The THPI targeting MMP-8 minimized lung damage, increased production of the anti-inflammatory cytokine IL-10, and vastly improved mouse survival.

PMID:
28394608
DOI:
10.1021/acs.jmedchem.7b00018
[Indexed for MEDLINE]

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