Validation of Matrix Metalloproteinase-9 (MMP-9) as a Novel Target for Treatment of Diabetic Foot Ulcers in Humans and Discovery of a Potent and Selective Small-Molecule MMP-9 Inhibitor That Accelerates Healing.

Journal of Medicinal Chemistry
Trung T NguyenMayland Chang

Abstract

Diabetic foot ulcers (DFUs) are a significant health problem. A single existing FDA-approved drug for this ailment, becaplermin, is not standard-of-care. We previously demonstrated that upregulation of active matrix metalloproteinase (MMP)-9 is the reason that the diabetic wound in mice is recalcitrant to healing and that MMP-8 participates in wound repair. In the present study, we validate the target MMP-9 by identifying and quantifying active MMP-8 and MMP-9 in human diabetic wounds using an affinity resin that binds exclusively to the active forms of MMPs coupled with proteomics. Furthermore, we synthesize and evaluate enantiomerically pure ( R)- and ( S)-ND-336, as inhibitors of the detrimental MMP-9, and show that the ( R)-enantiomer has superior efficacy in wound healing over becaplermin. Our results reveal that the mechanisms of pathology and repair are similar in diabetic mice and diabetic humans and that ( R)-ND-336 holds promise for the treatment of DFUs as a first-in-class therapeutic.

References

Nov 17, 1999·Wound Repair and Regeneration : Official Publication of the Wound Healing Society [and] the European Tissue Repair Society·J M SmiellB H Schwab
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Apr 28, 2004·Plastic and Reconstructive Surgery·Stephen R SullivanJohn E Olerud
Jul 28, 2005·The Journal of Biological Chemistry·Masahiro IkejiriShahriar Mobashery
Jul 29, 2006·The Journal of Organic Chemistry·Dusan HesekShahriar Mobashery
Aug 19, 2007·Seminars in Cell & Developmental Biology·Barbara Fingleton
Oct 12, 2007·Chemical Biology & Drug Design·Mijoon LeeMayland Chang
Feb 3, 2009·Toxicologic Pathology·Vanesa Ivetić TkalcevićKarmen Brajsa
Apr 7, 2010·Human Genomics·Brian C JacksonVasilis Vasiliou
Dec 15, 2010·Cell Research·Andy WullaertManolis Pasparakis
Dec 22, 2010·Advances in Skin & Wound Care·Najat ZiyadehJohn D Seeger
May 1, 2013·European Journal of Vascular and Endovascular Surgery : the Official Journal of the European Society for Vascular Surgery·L V FortingtonP U Dijkstra
Sep 24, 2013·ACS Chemical Biology·Major GooyitMayland Chang
Nov 5, 2013·Physiology·Andriy YabluchanskiyMerry L Lindsey
Mar 19, 2014·Diabetes Research and Clinical Practice·L GuariguataJ E Shaw
Feb 10, 2011·ACS Medicinal Chemistry Letters·Sebastian A TesteroMayland Chang
Nov 26, 2015·Proceedings of the National Academy of Sciences of the United States of America·Ming GaoMayland Chang
Dec 10, 2015·Diabetes·Marc A SoaresDaniel J Ceradini
Aug 24, 2016·ACS Chemical Neuroscience·Ming GaoMayland Chang
Jan 25, 2017·Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia·Nikola AmbrozovaAdela Galandakova
Jun 15, 2017·The New England Journal of Medicine·David G ArmstrongSicco A Bus
Aug 12, 2017·Biochimica Et Biophysica Acta. Molecular Cell Research·Venkat Raghavan KrishnaswamyIrit Sagi

❮ Previous
Next ❯

Citations

Nov 19, 2019·Wound Repair and Regeneration : Official Publication of the Wound Healing Society [and] the European Tissue Repair Society·Trung T NguyenMayland Chang
May 28, 2019·Pharmaceuticals·Jeffrey I JonesMayland Chang
Sep 10, 2020·MedChemComm·Geetha B KumarDavid B C Martin
Nov 22, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Ying WangXinwang Yang
Jan 26, 2021·Expert Opinion on Therapeutic Patents·Elena LenciAndrea Trabocchi
Feb 18, 2021·Accounts of Chemical Research·Mayland Chang, Trung T Nguyen
Mar 19, 2021·Science Translational Medicine·Simon MatooriDavid J Mooney
Apr 21, 2021·Regenerative Medicine·Damien P Kuffler
Jun 22, 2021·ACS Pharmacology & Translational Science·Charles Edwin Raja GabrielShahriar Mobashery
Aug 12, 2021·Molecular Biology Reports·Nabil M Abdel-Hamid, Shimaa A Abass

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.