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Structural basis for the inhibitory effects of a novel reversible covalent ligand on PPAR? phosphorylation.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is a major therapeutic target for the treatment of type 2 diabetes. However, the use of PPAR?-targeted drugs, such as rosiglitazone and pioglitazone, is limited owing to serious side effects caused by classical agonism. Using a rational drug discovery approach, we recently developed SB1495, a novel reversible covalent inhibitor of the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of PPAR? at Ser245, a key factor in the insulin-sensitizing effect of PPAR?-targeted drugs. In this study, we report the crystal structures of PPAR? in complex with SB1495 and its enantiomeric analogue SB1494, which rarely exhibits inhibitory activity, to visualize the mechanistic basis for their distinct activities. SB1495 occupies the Arm3 region near the ? loop of the PPAR? ligand-binding domain, whereas its enantiomeric analogue SB1494 binds to the Arm2 region. In addition, the piperazine moiety of SB1495 directly pushes the helix H2', resulting in the stabilization of the ? loop just behind the helix H2'. Our results may contribute to the development of a new generation of antidiabetic drugs that selectively block PPAR? phosphorylation without classical agonism.

SUBMITTER: Jang JY

PROVIDER: S-EPMC6671948 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Structural basis for the inhibitory effects of a novel reversible covalent ligand on PPARγ phosphorylation.

Jang Jun Young JY Kim Hyunsoo H Kim Hyun-Jung HJ Suh Se Won SW Park Seung Bum SB Han Byung Woo BW

Scientific reports 20190801 1

Peroxisome proliferator-activated receptor γ (PPARγ) is a major therapeutic target for the treatment of type 2 diabetes. However, the use of PPARγ-targeted drugs, such as rosiglitazone and pioglitazone, is limited owing to serious side effects caused by classical agonism. Using a rational drug discovery approach, we recently developed SB1495, a novel reversible covalent inhibitor of the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of PPARγ at Ser245, a key factor in the insulin-sens ...[more]

PMID: 31371757

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the viral pathogen causing the coronavirus disease 2019 (COVID-19) global pandemic. No effective treatment for COVID-19 has been established yet. The serine protease transmembrane protease serine 2 (TMPRSS2) is essential for viral spread and pathogenicity by facilitating the entry of SARS-CoV-2 into host cells. The protease inhibitor camostat, an anticoagulant used in the clinic, has potential anti-inflammatory and antiviral activities against COVID-19. However, the potential mechanisms of viral resistance and antiviral activity of camostat are unclear. Herein, we demonstrate high inhibitory potencies of camostat for a panel of serine proteases, indicating that camostat is a broad-spectrum inhibitor of serine proteases. In addition, we determined the crystal structure of camostat in complex with a serine protease (uPA [urokinase-type plasminogen activator]), which reveals that camostat is inserted in the S1 pocket of uPA but is hydrolyzed by uPA, and the cleaved camostat covalently binds to Ser195. We also generated a homology model of the structure of the TMPRSS2 serine protease domain. The model shows that camostat uses the same inhibitory mechanism to inhibit the activity of TMPRSS2, subsequently preventing SARS-CoV-2 spread. IMPORTANCE Serine proteases are a large family of enzymes critical for multiple physiological processes and proven diagnostic and therapeutic targets in several clinical indications. The serine protease transmembrane protease serine 2 (TMPRSS2) was recently found to mediate SARS-CoV-2 entry into the host. Camostat mesylate (FOY 305), a serine protease inhibitor active against TMPRSS2 and used for the treatment of oral squamous cell carcinoma and chronic pancreatitis, inhibits SARS-CoV-2 infection of human lung cells. However, the direct inhibition mechanism of camostat mesylate for TMPRSS2 is unclear. Herein, we demonstrate that camostat uses the same inhibitory mechanism to inhibit the activity of TMPRSS2 as uPA, subsequently preventing SARS-CoV-2 spread.

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Structural basis for the inhibitory effects of a novel reversible covalent ligand on PPAR? phosphorylation.

Publications

Structural basis for the inhibitory effects of a novel reversible covalent ligand on PPARγ phosphorylation.

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