Small-molecule inhibition of the archetypal UbiB protein COQ8

Nathan H. Murray; Christopher R.M. Asquith; Zixiang Fang; Michael P. East; Naomi Ptak; Robert W. Smith; James D. Vasta; Chad A. Zimprich; Cesear R. Corona; Matthew B. Robers; Gary L. Johnson; Craig A. Bingman; David J. Pagliarini

doi:10.1038/s41589-022-01168-3

Small-molecule inhibition of the archetypal UbiB protein COQ8

Nathan H. Murray, Christopher R.M. Asquith, Zixiang Fang, Michael P. East, Naomi Ptak, Robert W. Smith, James D. Vasta, Chad A. Zimprich, Cesear R. Corona, Matthew B. Robers, Gary L. Johnson, Craig A. Bingman, David J. Pagliarini

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Abstract

Small-molecule tools have enabled mechanistic investigations and therapeutic targeting of the protein kinase-like (PKL) superfamily. However, such tools are still lacking for many PKL members, including the highly conserved and disease-related UbiB family. Here, we sought to develop and characterize an inhibitor for the archetypal UbiB member COQ8, whose function is essential for coenzyme Q (CoQ) biosynthesis. Guided by crystallography, activity assays and cellular CoQ measurements, we repurposed the 4-anilinoquinoline scaffold to selectively inhibit human COQ8A in cells. Our chemical tool promises to lend mechanistic insights into the activities of these widespread and understudied proteins and to offer potential therapeutic strategies for human diseases connected to their dysfunction. [Figure not available: see fulltext.]

Original language	English
Pages (from-to)	230-238
Number of pages	9
Journal	Nature Chemical Biology
Volume	19
Issue number	2
DOIs	https://doi.org/10.1038/s41589-022-01168-3
State	Published - Feb 2023

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title = "Small-molecule inhibition of the archetypal UbiB protein COQ8",

abstract = "Small-molecule tools have enabled mechanistic investigations and therapeutic targeting of the protein kinase-like (PKL) superfamily. However, such tools are still lacking for many PKL members, including the highly conserved and disease-related UbiB family. Here, we sought to develop and characterize an inhibitor for the archetypal UbiB member COQ8, whose function is essential for coenzyme Q (CoQ) biosynthesis. Guided by crystallography, activity assays and cellular CoQ measurements, we repurposed the 4-anilinoquinoline scaffold to selectively inhibit human COQ8A in cells. Our chemical tool promises to lend mechanistic insights into the activities of these widespread and understudied proteins and to offer potential therapeutic strategies for human diseases connected to their dysfunction. [Figure not available: see fulltext.]",

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year = "2023",

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doi = "10.1038/s41589-022-01168-3",

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AU - Asquith, Christopher R.M.

AU - Fang, Zixiang

AU - East, Michael P.

AU - Ptak, Naomi

AU - Smith, Robert W.

AU - Vasta, James D.

AU - Zimprich, Chad A.

AU - Corona, Cesear R.

AU - Robers, Matthew B.

AU - Johnson, Gary L.

AU - Bingman, Craig A.

AU - Pagliarini, David J.

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AB - Small-molecule tools have enabled mechanistic investigations and therapeutic targeting of the protein kinase-like (PKL) superfamily. However, such tools are still lacking for many PKL members, including the highly conserved and disease-related UbiB family. Here, we sought to develop and characterize an inhibitor for the archetypal UbiB member COQ8, whose function is essential for coenzyme Q (CoQ) biosynthesis. Guided by crystallography, activity assays and cellular CoQ measurements, we repurposed the 4-anilinoquinoline scaffold to selectively inhibit human COQ8A in cells. Our chemical tool promises to lend mechanistic insights into the activities of these widespread and understudied proteins and to offer potential therapeutic strategies for human diseases connected to their dysfunction. [Figure not available: see fulltext.]

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Small-molecule inhibition of the archetypal UbiB protein COQ8

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