Screen for Small-Molecule Modulators of Circadian Rhythms Reveals Phenazine as a Redox-State Modifying Clockwork Tuner

Kevin P. Kelly; Hugo Borsetti; Marta E. Wenzler; Alessandro Ustione; Kwangho Kim; Plamen P. Christov; Bianca Ramirez; Joshua A. Bauer; David W. Piston; Carl Hirschie Johnson; Gary A. Sulikowski

doi:10.1021/acschembio.2c00240

Screen for Small-Molecule Modulators of Circadian Rhythms Reveals Phenazine as a Redox-State Modifying Clockwork Tuner

Kevin P. Kelly, Hugo Borsetti, Marta E. Wenzler, Alessandro Ustione, Kwangho Kim, Plamen P. Christov, Bianca Ramirez, Joshua A. Bauer, David W. Piston, Carl Hirschie Johnson, Gary A. Sulikowski

Research output: Contribution to journal › Article › peer-review

Abstract

A high-Throughput cell-based screen identified redox-Active small molecules that produce a period lengthening of the circadian rhythm. The strongest period lengthening phenotype was induced by a phenazine carboxamide (VU661). Comparison to two isomeric benzquinoline carboxamides (VU673 and VU164) shows the activity is associated with the redox modulating phenazine functionality. Furthermore, ex vivo cell analysis using optical redox ratio measurements shows the period lengthening phenotype to be associated with a shift to the NAD/FAD oxidation state of nicotinamide and flavine coenzymes.

Original language	English
Pages (from-to)	1658-1664
Number of pages	7
Journal	ACS Chemical Biology
Volume	17
Issue number	7
DOIs	https://doi.org/10.1021/acschembio.2c00240
State	Published - Jul 15 2022

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Kelly, K. P., Borsetti, H., Wenzler, M. E., Ustione, A., Kim, K., Christov, P. P., Ramirez, B., Bauer, J. A., Piston, D. W., Johnson, C. H., & Sulikowski, G. A. (2022). Screen for Small-Molecule Modulators of Circadian Rhythms Reveals Phenazine as a Redox-State Modifying Clockwork Tuner. ACS Chemical Biology, 17(7), 1658-1664. https://doi.org/10.1021/acschembio.2c00240

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abstract = "A high-Throughput cell-based screen identified redox-Active small molecules that produce a period lengthening of the circadian rhythm. The strongest period lengthening phenotype was induced by a phenazine carboxamide (VU661). Comparison to two isomeric benzquinoline carboxamides (VU673 and VU164) shows the activity is associated with the redox modulating phenazine functionality. Furthermore, ex vivo cell analysis using optical redox ratio measurements shows the period lengthening phenotype to be associated with a shift to the NAD/FAD oxidation state of nicotinamide and flavine coenzymes.",

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AU - Kelly, Kevin P.

AU - Borsetti, Hugo

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AU - Ustione, Alessandro

AU - Kim, Kwangho

AU - Christov, Plamen P.

AU - Ramirez, Bianca

AU - Bauer, Joshua A.

AU - Piston, David W.

AU - Johnson, Carl Hirschie

AU - Sulikowski, Gary A.

PY - 2022/7/15

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AB - A high-Throughput cell-based screen identified redox-Active small molecules that produce a period lengthening of the circadian rhythm. The strongest period lengthening phenotype was induced by a phenazine carboxamide (VU661). Comparison to two isomeric benzquinoline carboxamides (VU673 and VU164) shows the activity is associated with the redox modulating phenazine functionality. Furthermore, ex vivo cell analysis using optical redox ratio measurements shows the period lengthening phenotype to be associated with a shift to the NAD/FAD oxidation state of nicotinamide and flavine coenzymes.

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Screen for Small-Molecule Modulators of Circadian Rhythms Reveals Phenazine as a Redox-State Modifying Clockwork Tuner

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