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Open AccessArticle

Matrix Metalloproteinase Triple-Helical Peptide Inhibitors: Potential Cross-Reactivity with Caspase-11

1
Department of Chemistry & Biochemistry, Florida Atlantic University, 5353 Parkside Drive, Jupiter, FL 33458, USA
2
Department of Chemistry, The Scripps Research Institute/Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(23), 4355; https://doi.org/10.3390/molecules24234355
Received: 30 October 2019 / Revised: 25 November 2019 / Accepted: 26 November 2019 / Published: 28 November 2019
(This article belongs to the Special Issue Drug Design)
Triple-helical peptide inhibitors (THPIs) of matrix metalloproteinases (MMPs) have recently been demonstrated to be effective in a variety of animal models of disease, coincidental with knockout studies. However, passenger mutations have been described in MMP knockout mice that impact the activity of other proteins, including caspase-11. Thus, it is possible that the results observed with THPIs may be based on inhibition of caspase-11, not MMPs. The present study evaluated whether THPIs were cross-reactive with caspase-11. Two different THPIs were tested, one that is known to inhibit MMP-1 and MMP-8 (GlyΨ{PO2H-CH2}Ile-His-Lys-Gln THPI) and one that is selective for MMP-2 and MMP-9 (α1(V)GlyΨ{PO2H-CH2}Val [mep14,32,Flp15,33] THPI). No inhibition of caspase-11 was observed with GlyΨ{PO2H–CH2}Ile–His–Lys–Gln THPI, even at an inhibitor concentration of 5 μM, while 5 μM α1(V)GlyΨ{PO2H-CH2}Val [mep14,32,Flp15,33] THPI exhibited 40% inhibition of caspase-11. Further testing of GlyΨ{PO2H-CH2}Ile-His-Lys-Gln THPI revealed nM inhibition of MMP-2, MMP-9, and MMP-13. Thus, the effectiveness of GlyΨ{PO2H-CH2}Ile-His-Lys-Gln THPI observed in a sepsis animal model may not be due to caspase-11 inhibition, but may be due to broader MMP inhibition than previously thought. View Full-Text
Keywords: matrix metalloproteinase; caspase; sepsis; phosphinate; protease inhibitor; triple-helical peptide inhibitor matrix metalloproteinase; caspase; sepsis; phosphinate; protease inhibitor; triple-helical peptide inhibitor
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Knapinska, A.M.; Hart, M.; Drotleff, G.; Fields, G.B. Matrix Metalloproteinase Triple-Helical Peptide Inhibitors: Potential Cross-Reactivity with Caspase-11. Molecules 2019, 24, 4355.

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