Therapeutic Targeting of MMP-12 for the Treatment of Chronic Obstructive Pulmonary Disease.

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Abstrakt

Tytuł:: Therapeutic Targeting of MMP-12 for the Treatment of Chronic Obstructive Pulmonary Disease.
Autorzy:: Baggio C; Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, California 92521, United States.
Velazquez JV; Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, California 92521, United States.
Fragai M; Magnetic Resonance Center (CERM), University of Florence and Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy.
Nordgren TM; Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, California 92521, United States.
Pellecchia M; Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, California 92521, United States.
Źródło:: Journal of medicinal chemistry [J Med Chem] 2020 Nov 12; Vol. 63 (21), pp. 12911-12920. Date of Electronic Publication: 2020 Oct 27.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural
Język:: English
Imprint Name(s):: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
MeSH Terms:: Matrix Metalloproteinase 12/*metabolism
Matrix Metalloproteinase Inhibitors/*chemistry
Animals ; Binding Sites ; Crystallography, X-Ray ; Disease Models, Animal ; Emphysema/drug therapy ; Emphysema/etiology ; Half-Life ; Humans ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/metabolism ; Matrix Metalloproteinase 12/chemistry ; Matrix Metalloproteinase Inhibitors/pharmacokinetics ; Matrix Metalloproteinase Inhibitors/therapeutic use ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Molecular Dynamics Simulation ; Nuclear Magnetic Resonance, Biomolecular ; Pancreatic Elastase/metabolism ; Peptides/genetics ; Peptides/metabolism ; Peptides/therapeutic use ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Pulmonary Disease, Chronic Obstructive/pathology ; Structure-Activity Relationship
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Grant Information:: P20 CA242620 United States CA NCI NIH HHS; R00 ES025819 United States ES NIEHS NIH HHS; R01 CA168517 United States CA NCI NIH HHS; R01 NS107479 United States NS NINDS NIH HHS
Substance Nomenclature:: 0 (Isoenzymes)
0 (Matrix Metalloproteinase Inhibitors)
0 (Peptides)
EC 3.4.21.36 (Pancreatic Elastase)
EC 3.4.24.65 (Matrix Metalloproteinase 12)
Entry Date(s):: Date Created: 20201027 Date Completed: 20201218 Latest Revision: 20211113
Update Code:: 20240105
PubMed Central ID:: PMC8544245
DOI:: 10.1021/acs.jmedchem.0c01285
PMID:: 33107733
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Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by progressive airflow obstruction associated with inflammation and emphysema, and it is currently one of the leading causes of death worldwide. Recent studies with genetically engineered mice reported that during pulmonary inflammation, basophil-derived interleukin-4 can act on lung-infiltrating monocytes causing aberrant expression of the matrix metalloproteinase-12 (MMP-12). MMP-12 activity in turn causes the destruction of alveolar walls leading to emphysema, making it potentially a valid target for pharmacological intervention. Using nuclear magnetic resonance (NMR)- and structure-based optimizations, the current study reports on the optimized novel, potent, and selective MMP-12 inhibitors with single-digit nanomolar affinity in vitro and in vivo efficacy. Using a murine model of elastase-induced emphysema we demonstrated that the most potent agents exhibited a significant decrease in emphysema-like pathology compared to vehicle-treated mice, thus suggesting that the reported agents may potentially be translated into novel therapeutics for the treatment of COPD.

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