Matrix Metalloproteinase Inhibition by Heterotrimeric Triple‐Helical Peptide Transition State Analogues

Bhowmick, Manishabrata; Stawikowska, Roma; Tokmina‐Roszyk, Dorota; Fields, Gregg B.

doi:10.1002/cbic.201402716

Cited by 20 publications

(21 citation statements)

References 52 publications

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“…Inhibition of MMPs by RTD-1 was performed as described [ 24 ], incubating each enzyme with 0–100 μg/ml of RTD-1. IC 50 values were calculated by GraphPad Prism 5.01 (GraphPad Software, San Diego, CA) utilizing a non-linear curve fit of log [inhibitor] versus response with variable slope.…”

Section: Methodsmentioning

confidence: 99%

Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide

et al. 2017

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θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus θ-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA). Parenteral RTD-1 treatment of DA/OlaHsd rats with established pristane-induced arthritis (PIA) rapidly suppressed joint disease progression, restored limb mobility, and preserved normal joint architecture. RTD-1 significantly reduced joint IL-1β levels compared with controls. RTD-1 dose-dependently inhibited fibroblast-like synoviocyte (FLS) invasiveness and FLS IL-6 production. Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFα, and inhibited matrix metalloproteases, and cathepsin K. RTD-1 was non-toxic, non-immunogenic, and effective when administered as infrequently as once every five days. Thus θ-defensins, which are absent in humans, have potential as retroevolutionary biologics for the treatment of RA.

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Section: Methodsmentioning

confidence: 99%

Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide

et al. 2017

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“…Phosphinic peptides offer the possibility of interacting with both the primed and unprimed sides of the MMP active site cleft [43]. We have reported that phosphinic triple-helical peptides (THPs) behave as effective transition state analog inhibitors of collagenolytic MMPs [67,149,150,151,152]. These triple-helical peptide inhibitors (THPIs) have proven effective in mouse models of multiple sclerosis, sepsis, and myocardial infarction [67,153].…”

Section: Development Of Improved Mmp Inhibitorsmentioning

confidence: 99%

The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma

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2019

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The pursuit of matrix metalloproteinase (MMP) inhibitors began in earnest over three decades ago. Initial clinical trials were disappointing, resulting in a negative view of MMPs as therapeutic targets. As a better understanding of MMP biology and inhibitor pharmacokinetic properties emerged, it became clear that initial MMP inhibitor clinical trials were held prematurely. Further complicating matters were problematic conclusions drawn from animal model studies. The most recent generation of MMP inhibitors have desirable selectivities and improved pharmacokinetics, resulting in improved toxicity profiles. Application of selective MMP inhibitors led to the conclusion that MMP-2, MMP-9, MMP-13, and MT1-MMP are not involved in musculoskeletal syndrome, a common side effect observed with broad spectrum MMP inhibitors. Specific activities within a single MMP can now be inhibited. Better definition of the roles of MMPs in immunological responses and inflammation will help inform clinic trials, and multiple studies indicate that modulating MMP activity can improve immunotherapy. There is a U.S. Food and Drug Administration (FDA)-approved MMP inhibitor for periodontal disease, and several MMP inhibitors are in clinic trials, targeting a variety of maladies including gastric cancer, diabetic foot ulcers, and multiple sclerosis. It is clearly time to move on from the dogma of viewing MMP inhibition as intractable.

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“…Phosphinic dipeptides contain a hydrolytically stable, tetrahedral phosphinic moiety that mimics the tetrahedral intermediate formed during enzymatic hydrolysis. Previously, we reported that phosphinic triple-helical peptides (THPs) behave as effective transition state analog inhibitors of collagenolytic MMPs 12,14,15. More specifically, two homotrimeric triple-helical peptide inhibitors (THPIs), C 6 -(Gly-Pro-Hyp) 4 -Gly-Pro-Pro-Gly Ψ {PO 2 H-CH 2 }Val-Val-Gly-Glu-Gln-Gly-Glu-Gln-Gly-Pro-Pro-(Gly-Pro-Hyp) 4 -NH 2 [designated C 6 - α 1(V)Gly Ψ {PO 2 H-CH 2 }Val THPI] and (Gly-Pro-Hyp) 4 -Gly-mep-Flp-Gly-Pro-Gln-Gly Ψ {PO 2 H-CH 2 }Leu-Ala-Gly-Gln-Arg-Gly-Ile-Arg-Gly-mep-Flp-(Gly-Pro-Hyp) 4 -Tyr-NH 2 [designated α 1(I-III)Gly Ψ {PO 2 H-CH 2 }Leu THPI], were shown to inhibit MMPs in the low nanomolar range 12,14.…”

Section: Introductionmentioning

confidence: 99%

Second Generation Triple-Helical Peptide Inhibitors of Matrix Metalloproteinases

et al. 2017

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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.

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Matrix Metalloproteinase Inhibition by Heterotrimeric Triple‐Helical Peptide Transition State Analogues

Cited by 20 publications

References 52 publications

Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide

Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide

The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma

Second Generation Triple-Helical Peptide Inhibitors of Matrix Metalloproteinases

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