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

Anna M Knapinska,Gary Drotleff,Gregg B Fields,Melissa Hart

doi:10.3390/molecules24234355

Anna M Knapinska, Gary Drotleff + Show 2 more

Open Access

https://doi.org/10.3390/molecules24234355

Copy DOI

Abstract

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.

Highlights

The matrix metalloproteinase (MMP) family of enzymes has been implicated in a great variety of diseases [1,2,3,4,5,6], resulting in the pursuit of matrix metalloproteinases (MMPs) inhibitors that has spanned decades [1,7,8,9,10,11,12]
We have reported that phosphinic triple-helical peptides (THPs) behave as effective transition state analog inhibitors of collagenolytic MMPs [15,16,17,18,19]
The present study has examined the inhibition of (a) caspase-11 by two phosphinate-based Triple-helical peptide inhibitors (THPIs) and (b) other collagenolytic MMPs by GlyΨ{PO2 H-CH2 }Ile-His-Lys-Gln THPI

Summary

Introduction

The matrix metalloproteinase (MMP) family of enzymes has been implicated in a great variety of diseases [1,2,3,4,5,6], resulting in the pursuit of MMP inhibitors that has spanned decades [1,7,8,9,10,11,12]. A variety of phosphorus-based peptides have been developed as MMP inhibitors [7,13,14]. We have reported that phosphinic triple-helical peptides (THPs) behave as effective transition state analog inhibitors of collagenolytic MMPs [15,16,17,18,19]. Gene ablation studies have indicated that MMP-8 facilitates sepsis in animal models, while MT1-MMP is protective [19,20,21]. GlyΨ{PO2 H-CH2 }Ile-His-Lys-Gln THPI was applied in an animal model of sepsis [19]. Using the cecal ligation and puncture (CLP) sepsis model, 70% of the wild-type

Methods

Results

Conclusion