Inhibition of Connexin Hemichannels by New Amphiphilic Aminoglycosides without Antibiotic Activity.

Autor:	AlFindee MN; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, United States.; Department of Pharmaceutical Chemistry, College of Pharmacy, University of Basra, Basra, Iraq., Subedi YP; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, United States., Fiori MC; Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, Texas 79430-6551, United States., Krishnan S; Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, Texas 79430-6551, United States., Kjellgren A; Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, Texas 79430-6551, United States.; Honors College, McClellan Hall, Box 41017, Texas Tech University, Lubbock, Texas 79409-1017, United States., Altenberg GA; Department of Cell Physiology and Molecular Biophysics, and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, Texas 79430-6551, United States., Chang CT; Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Jun 19; Vol. 9 (7), pp. 697-701. Date of Electronic Publication: 2018 Jun 19 (Print Publication: 2018).
DOI:	10.1021/acsmedchemlett.8b00158
Abstrakt:	Connexins hemichannels (HCs) from adjacent cells form gap junctional channels that mediate cell-to-cell communication. Abnormal opening of "free" undocked HCs can produce cell damage and participate in the mechanism of disorders such as cardiac infarct, stroke, deafness, skin diseases, and cataracts. Therefore, inhibitors of connexin HCs have great pharmacological potential. Antibiotic aminoglycosides (AGs) have been recently identified as connexin HC inhibitors, but their antibiotic effect is an issue for the treatment of disorders where infections do not play a role. Herein, we synthesized and tested several amphiphilic AGs without antibiotic effect for their inhibition against connexin HCs, using a newly developed cell-based bacterial growth complementation assay. Several leads with superior potency than the parent compound, kanamycin A, were identified. Unlike traditional AGs, these amphiphilic AGs are not bactericidal and are not toxic to mammalian cells, making them better than traditional AGs as HC inhibitors for clinical use and other applications. Competing Interests: The authors declare no competing financial interest.
Databáze:	MEDLINE
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