Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence.
Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence.
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DOI：
10.1021/acs.jmedchem.2c01789
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发表时间：
2023-01-12
影响因子：
7.3
通讯作者：
Cheng, Xiaodong
中科院分区：
文献类型：
--
作者：
Zhou, Jujun;Horton, John R.;Menna, Martina;Fiorentino, Francesco;Ren, Ren;Yu, Dan;Hajian, Taraneh;Vedadi, Masoud;Mazzoccanti, Giulia;Ciogli, Alessia;Weinhold, Elmar;Hueben, Michael;Blumenthal, Robert M.;Zhang, Xing;Mai, Antonello;Rotili, Dante;Cheng, Xiaodong
迫切需要靶向内孢子传播的艰难梭菌感染的抗病毒剂。C.艰难梭菌特异性DNA腺嘌呤甲基转移酶（CamA）是有效孢子形成所必需的，并影响在结肠中的持久性。CamA的活性位点是保守的，并且与数百种相关的S-腺苷-L-甲硫氨酸（SAM）依赖性甲基转移酶的活性位点非常相似，这使得选择性抑制剂的设计更具挑战性。我们探索了溶剂暴露的SAM腺苷部分的边缘，并系统地设计了42个类似物的腺苷携带取代基在C6-氨基（N6）的腺苷。我们比较了这些不同化合物的抑制特性和结合亲和力，并在底物DNA的存在下，与其中14种化合物复合，呈现CamA的晶体结构。这些抑制剂中最有效的化合物39（IC 50 ≤ 0.4 μM，KD ≤ 0.2 μM）对CamA具有选择性，可抑制与细菌和哺乳动物密切相关的DNA和RNA腺嘌呤甲基转移酶、蛋白质赖氨酸和精氨酸甲基转移酶以及人腺苷受体。
Antivirulence agents targeting endospore-transmitted Clostridioides difficile infections are urgently needed. C. difficile-specific DNA adenine methyltransferase (CamA) is required for efficient sporulation and affects persistence in the colon. The active site of CamA is conserved and closely resembles those of hundreds of related S-adenosyl-l-methionine (SAM)-dependent methyltransferases, which makes the design of selective inhibitors more challenging. We explored the solvent-exposed edge of the SAM adenosine moiety and systematically designed 42 analogs of adenosine carrying substituents at the C6-amino group (N6) of adenosine. We compare the inhibitory properties and binding affinity of these diverse compounds and present the crystal structures of CamA in complex with 14 of them in the presence of substrate DNA. The most potent of these inhibitors, compound 39 (IC50 ∼ 0.4 μM and KD ∼ 0.2 μM), is selective for CamA against closely related bacterial and mammalian DNA and RNA adenine methyltransferases, protein lysine and arginine methyltransferases, and human adenosine receptors.
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美国梭菌艰难梭菌感染和结果负担的趋势。
DOI：
10.1056/nejmoa1910215
发表时间：
2020-04-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guh AY;Mu Y;Winston LG;Johnston H;Olson D;Farley MM;Wilson LE;Holzbauer SM;Phipps EC;Dumyati GK;Beldavs ZG;Kainer MA;Karlsson M;Gerding DN;McDonald LC;Emerging Infections Program Clostridioides difficile Infection Working Group
通讯作者：
Emerging Infections Program Clostridioides difficile Infection Working Group
影响因子：
7.3
作者：
Horton JR;Woodcock CB;Chen Q;Liu X;Zhang X;Shanks J;Rai G;Mott BT;Jansen DJ;Kales SC;Henderson MJ;Cyr M;Pohida K;Hu X;Shah P;Xu X;Jadhav A;Maloney DJ;Hall MD;Simeonov A;Fu H;Vertino PM;Cheng X
通讯作者：
Cheng X
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
16
作者：
Cao, R;Zhang, Y
通讯作者：
Zhang, Y
影响因子：
7.3
作者：
Bressi, JC;Choe, J;Gelb, MH
通讯作者：
Gelb, MH