Selective Water-Soluble Gelatinase Inhibitor Prodrugs

Gooyit, Major; Lee, Mijoon; Schroeder, Valerie A.; Ikejiri, Masahiro; Suckow, Mark A.; Mobashery, Shahriar; Chang, Mayland

doi:10.1021/jm200566e

Cited by 45 publications

(63 citation statements)

References 41 publications

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“…However, since we were unsuccessful in demonstrating a significant reduction in cleaved MMP-9 activity 6 h after HI, we cannot discount the possibility that any remaining cleaved MMP-9 activity was at levels sufficient to counteract potential neuroprotective effects of SB-3CT. Given the lack of neuroprotection found with SB-3CT further investigations are warranted using recently developed selective water-soluble MMP gelatinase inhibitors that can be administered intravenously to evaluate the possibility of significant neuroprotection [38]. …”

Section: Discussionmentioning

confidence: 99%

Inhibition of MMP-9 Activity following Hypoxic Ischemia in the Developing Brain Using a Highly Specific Inhibitor

Ranasinghe¹,

Scheepens

Sirimanne³

et al. 2012

Dev Neurosci

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Perinatal hypoxic ischemic (HI) brain injury is a leading cause of long-term neurological handicap in newborn babies. Recently, excessive activity of matrix metalloproteinases (MMPs), and in particular MMP-9, has been implicated in the aetiology of HI injuries to the immature brain. Our previous study suggested that MMP-9 may be involved in the development of the delayed injury processes following HI injury to the developing brain. Given this, we therefore propose that MMP-9 may be a useful target for rescue therapies in the injured developing brain. To address this, we chose to use SB-3CT, a highly selective inhibitor that is known to target only MMP-2 and MMP-9, to attenuate the elevated MMP-9 activity seen following HI injury to the developing brain. Twenty-one-day-old postnatal Wistar rats were subjected to unilateral carotid artery occlusion followed by exposure to hypoxia (8% oxygen for 1 h). SB-3CT (50 mg/kg body weight in 25% dimethyl sulphoxide/75% polyethylene glycol) or an equal volume of vehicle or saline diluent was then administered intraperitoneally at 2, 5 and 14 h following the insult. Gelatin zymography revealed that pro-MMP-9 levels were significantly reduced at 6 h following hypoxic ischaemia (p ≤ 0.05). However, our results showed that despite significantly inhibiting brain pro-MMP-9 activity after hypoxic ischaemia, SB-3CT failed to confer significant neuroprotection in postnatal day 21 rats 3 days after an HI insult. Further investigations are warranted using a recently reported selective water-soluble version of SB-3CT or another MMP-9 selective inhibitor to resolve the role of MMP-9 in the aetiology of HI injury in the developing brain.

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Section: Discussionmentioning

confidence: 99%

Inhibition of MMP-9 Activity following Hypoxic Ischemia in the Developing Brain Using a Highly Specific Inhibitor

Ranasinghe¹,

Scheepens

Sirimanne³

et al. 2012

Dev Neurosci

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“…Over the past several years we have produced a library of thiirane inhibitors for MMPs (10)(11)(12), which allowed the identification of specific inhibitors for selective inhibition of enzymes involved in various MMP-mediated diseases. The thiiranes undergo a reaction catalyzed by the target MMP, resulting in opening of the thiirane ring and generation of the thiolate, which is a tight-binding inhibitor (13).…”

Section: Significancementioning

confidence: 99%

“…Excisional wounds were made on the dorsal thorax of db/db mice, and the wounds were treated topically with vehicle, ND-336, or ND-322 (compound 2), which was used as a positive control. ND-322 inhibits MMP-9 as a slow-binding inhibitor with a K i of 870 ± 110 nM and inhibits MMP-8 as a linear noncompetitive inhibitor with a K i of 2,600 ± 400 nM, with a threefold selectivity for MMP-9 over MMP-8 (10). Wounds treated with ND-336 healed 1.2-to 1.6-fold faster than those treated with ND-322 and twofold faster than those treated with vehicle ( Fig.…”

Section: Significancementioning

confidence: 99%

Acceleration of diabetic wound healing using a novel protease–anti-protease combination therapy

Gao

Nguyen

Suckow

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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152

147

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Nonhealing chronic wounds are major complications of diabetes resulting in >70,000 annual lower-limb amputations in the United States alone. The reasons the diabetic wound is recalcitrant to healing are not fully understood, and there are limited therapeutic agents that could accelerate or facilitate its repair. We previously identified two active forms of matrix metalloproteinases (MMPs), MMP-8 and MMP-9, in the wounds of db/db mice. We argued that the former might play a role in the body's response to wound healing and that the latter is the pathological consequence of the disease with detrimental effects. Here we demonstrate that the use of compound ND-336, a novel highly selective inhibitor of gelatinases (MMP-2 and MMP-9) and MMP-14, accelerates diabetic wound healing by lowering inflammation and by enhancing angiogenesis and re-epithelialization of the wound, thereby reversing the pathological condition. The detrimental role of MMP-9 in the pathology of diabetic wounds was confirmed further by the study of diabetic MMP-9-knockout mice, which exhibited wounds more prone to healing. Furthermore, topical administration of active recombinant MMP-8 also accelerated diabetic wound healing as a consequence of complete re-epithelialization, diminished inflammation, and enhanced angiogenesis. The combined topical application of ND-336 (a small molecule) and the active recombinant MMP-8 (an enzyme) enhanced healing even more, in a strategy that holds considerable promise in healing of diabetic wounds.

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“…Therefore, design of selective inhibitors against target MMPs that have tumor-promoting effects is needed. Pioneer studies aiming to develop selective MMP inhibitors recently have been reported (12)(13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

Molecular Design of a Highly Selective and Strong Protein Inhibitor against Matrix Metalloproteinase-2 (MMP-2)

Higashi

Hirose

Takeuchi

et al. 2013

Journal of Biological Chemistry

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Background: Lack of enzyme selectivity has been a major obstacle in developing MMP inhibitors into drugs. Results: A fusion protein consisting of APP-IP and TIMP-2 has a highly selective inhibitory activity against MMP-2. Conclusion: The exosite-assisted inhibitory mechanism makes APP-IP-TIMP-2 a highly selective inhibitor. Significance: APP-IP-TIMP-2 may be developed as an effective drug for treatment of diseases in which MMP-2 activity is involved.

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Selective Water-Soluble Gelatinase Inhibitor Prodrugs

Cited by 45 publications

References 41 publications

Inhibition of MMP-9 Activity following Hypoxic Ischemia in the Developing Brain Using a Highly Specific Inhibitor

Inhibition of MMP-9 Activity following Hypoxic Ischemia in the Developing Brain Using a Highly Specific Inhibitor

Acceleration of diabetic wound healing using a novel protease–anti-protease combination therapy

Molecular Design of a Highly Selective and Strong Protein Inhibitor against Matrix Metalloproteinase-2 (MMP-2)

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