Targeting the pregnane X receptor using microbial metabolite mimicry

被引：62

作者：

Dvorak, Zdenek ^{[1
]}

Kopp, Felix ^{[2
]}

Costello, Cait M. ^{[3
]}

Kemp, Jazmin S. ^{[3
]}

Li, Hao ^{[4
]}

Vrzalova, Aneta ^{[1
]}

Stepankova, Martina ^{[1
]}

Bartonkova, Iveta ^{[1
]}

Jiskrova, Eva ^{[1
]}

Poulikova, Karolina ^{[1
]}

Vyhlidalova, Barbora ^{[1
]}

Nordstroem, Lars U. ^{[2
]}

Karunaratne, Chamini, V ^{[2
]}

Ranhotra, Harmit S. ^{[4
,24
]}

Mun, Kyu Shik ^{[5
]}

Naren, Anjaparavanda P. ^{[5
]}

Murray, Iain A. ^{[6
]}

Perdew, Gary H. ^{[6
]}

Brtko, Julius ^{[7
]}

Toporova, Lucia ^{[7
]}

Schon, Arne ^{[8
]}

Wallace, William G. ^{[9
]}

Walton, William G. ^{[9
]}

Redinbo, Matthew R. ^{[9
]}

Sun, Katherine ^{[10
]}

Beck, Amanda ^{[11
]}

Kortagere, Sandhya ^{[12
]}

Neary, Michelle C. ^{[13
]}

Chandran, Aneesh ^{[14
]}

Vishveshwara, Saraswathi ^{[14
]}

Cavalluzzi, Maria M. ^{[15
]}

Lentini, Giovanni ^{[15
]}

Cui, Julia Yue ^{[16
]}

Gu, Haiwei ^{[17
]}

March, John C. ^{[3
]}

Chatterjee, Shirshendu ^{[18
,19
]}

Matson, Adam ^{[20
]}

Wright, Dennis ^{[21
]}

Flannigan, Kyle L. ^{[22
]}

Hirota, Simon A. ^{[22
]}

Sartor, Ryan Balfour ^{[23
]}

Mani, Sridhar ^{[4
]}

机构：

[1] Palacky Univ, Dept Cell Biol & Genet, Olomouc, Czech Republic

[2] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10467 USA

[3] Cornell Univ, Dept Biol & Environm Engn, Ithaca, NY USA

[4] Albert Einstein Coll Med, Dept Med Genet & Mol Pharmacol, Bronx, NY 10467 USA

[5] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA

[6] Penn State Coll Agr Sci, Dept Vet & Biomed Sci, University Pk, PA USA

[7] Slovak Acad Sci, Biomed Res Ctr, Inst Expt Endocrinol, Bratislava, Slovakia

[8] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA

[9] Univ N Carolina, Dept Chem, Chapel Hill, NC 27515 USA

[10] NYU, Sch Med, Dept Pathol, New York, NY USA

[11] Albert Einstein Coll Med, Dept Pathol, Bronx, NY USA

[12] Drexel Univ, Coll Med, Dept Microbiol & Immunol, Philadelphia, PA 19104 USA

[13] CUNY Hunter Coll, Dept Chem, New York, NY 10021 USA

[14] Indian Inst Sci, Mol Biophys Unit, Bangalore, Karnataka, India

[15] Univ Bari Aldo Moro, Dept Pharm Pharmaceut Sci, Bari, Italy

[16] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA

[17] Arizona State Univ, Coll Hlth Solut, Ctr Metab & Vasc Biol, Scottsdale, AZ USA

[18] CUNY, City Coll, New York, NY 10021 USA

[19] CUNY, Grad Ctr, New York, NY USA

[20] Univ Connecticut, Dept Pediat & Immunol, Farmington, CT USA

[21] Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT USA

[22] Univ Calgary, Dept Physiol & Pharmacol, Calgary, AB, Canada

[23] Univ North Carolina Chapel Hill, Dept Med, Div Gastroenterol & Hepatol, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC USA

[24] St Edmunds Coll, Shillong, Meghalaya, India

来源：

EMBO MOLECULAR MEDICINE | 2020年 / 12卷 / 04期

基金：

加拿大自然科学与工程研究理事会;

关键词：

drugs; microbial metabolite; mimics; pregnane X receptor; therapy; ARYL-HYDROCARBON RECEPTOR; INDUCE CYP1A GENES; HEPATOMA-CELL LINE; ST JOHNS WORT; NUCLEAR RECEPTORS; TRANSCRIPTIONAL ACTIVITY; DRUG-METABOLISM; ACTIVATION; PXR; MODEL;

D O I：

10.15252/emmm.201911621

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR-specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.

引用

页数：19

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