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Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy.

ABSTRACT: Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents. Currently, small-molecule inhibitors do not show good selectivity for different IMPDH isoforms (IMPDH1 and IMPDH2), resulting in some adverse effects, which limit their use. Herein, we used a small-molecule probe specifically targeting IMPDH2 and identified Cysteine residue 140 (Cys140) as a selective druggable site. On covalently binding to Cys140, the probe exerts an allosteric regulation to block the catalytic pocket of IMPDH2 and further induces IMPDH2 inactivation, leading to an effective suppression of neuroinflammatory responses. However, the probe does not covalently bind to IMPDH1. Taken together, our study shows Cys140 as a druggable site for selectively inhibiting IMPDH2, which provides great potential for development of therapy agents for autoimmune and neuroinflammatory diseases with less unfavorable tolerability profile.

SUBMITTER: Liao LX

PROVIDER: S-EPMC5530702 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy.

Liao Li-Xi LX Song Xiao-Min XM Wang Li-Chao LC Lv Hai-Ning HN Chen Jin-Feng JF Liu Dan D Fu Ge G Zhao Ming-Bo MB Jiang Yong Y Zeng Ke-Wu KW Tu Peng-Fei PF

Proceedings of the National Academy of Sciences of the United States of America 20170703 29

Inosine monophosphate dehydrogenase (IMPDH) of human is an attractive target for immunosuppressive agents. Currently, small-molecule inhibitors do not show good selectivity for different IMPDH isoforms (IMPDH1 and IMPDH2), resulting in some adverse effects, which limit their use. Herein, we used a small-molecule probe specifically targeting IMPDH2 and identified Cysteine residue 140 (Cys140) as a selective druggable site. On covalently binding to Cys140, the probe exerts an allosteric regulation ...[more]

PMID: 28674004

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Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy.

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Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy.

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