DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 M(pro) inhibitors.
DNA-encoded chemistry technology yields expedient access to SARS-CoV-2 M(pro) inhibitors.
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DOI：
10.1073/pnas.2111172118
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发表时间：
2021-09-07
影响因子：
11.1
通讯作者：
Young DW
中科院分区：
文献类型：
--
作者：
Chamakuri S;Lu S;Ucisik MN;Bohren KM;Chen YC;Du HC;Faver JC;Jimmidi R;Li F;Li JY;Nyshadham P;Palmer SS;Pollet J;Qin X;Ronca SE;Sankaran B;Sharma KL;Tan Z;Versteeg L;Yu Z;Matzuk MM;Palzkill T;Young DW
SARS-CoV-2对全球人类生活产生了严重影响。疫苗开发已被用作预防和缓解COVID-19的一线策略;然而，小分子药物仍然是扩大治疗选择的关键。用于鉴定生物活性小分子的传统筛选方法是缓慢的，并且通常对不足以鉴定合适命中的化合物进行取样。在这里，我们应用了一种被称为DNA编码化学技术（DEC-Tec）的筛选方法来筛选数十亿种针对关键病毒蛋白Mpro的化合物。在快速的方式中，我们鉴定了化合物CDD-1713作为有效的和选择性的Mpro抑制剂。这项研究阐明了DEC-Tec作为一种高效的策略，用于产生针对感染因子关键靶标的小分子。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）已在全球范围内造成400多万人死亡，但目前还没有真正的食品和药物管理局批准的药物样分子来阻止COVID-19大流行。传统治疗方法发现的缓慢步伐不适合针对快速进化的病毒进行靶向治疗。在这里，我们使用了基于亲和力的40亿DNA编码分子的筛选，以确定一类有效的SARS-CoV-2主要蛋白酶（Mpro）的病毒特异性抑制剂，而无需大量和耗时的药物化学。CDD-1714是最初的三个构件筛选命中物（分子量[MW] = 542.5 g/mol），是一种有效的抑制剂（抑制常数[Ki] = 20 nM）。CDD-1713是CDD-1714的一种较小的双结构单元类似物（MW = 353.3 g/mol），是Mpro的可逆共价抑制剂（Ki = 45 nM），结合在蛋白酶口袋中，对人类蛋白酶具有特异性，并在SARS-CoV-2感染模型中显示出体外疗效。随后，确定了抑制活性所必需的CDD-1713的关键区域，并产生了有效（Ki = 37 nM），较小（MW = 323.4 g/mol）和代谢更稳定的类似物（CDD-1976）。因此，筛选DNA编码的化学文库可以加速发现新出现的病毒性疾病靶标的有效药物样抑制剂。
SARS-CoV-2 has had a crippling impact on human life globally. Vaccine development has been used as a first-line strategy for COVID-19 prevention and mitigation; however, small-molecule drugs are still vitally needed to extend treatment options. Traditional screening methods for identifying biologically active small molecules are sluggish and often sample an insufficient number of compounds to identify suitable hits. Here, we applied a screening method known as DNA-encoded chemistry technology (DEC-Tec) to screen billions of compounds against a critical viral protein, Mpro. In rapid fashion, we identified the compound CDD-1713 as a potent and selective Mpro inhibitor. This study illuminates DEC-Tec as a highly expeditious strategy toward generating small molecules against critical targets of infectious agents. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration–approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [Ki] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of Mpro (Ki = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent (Ki = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets.
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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：
16.6
作者：
Douangamath A;Fearon D;Gehrtz P;Krojer T;Lukacik P;Owen CD;Resnick E;Strain-Damerell C;Aimon A;Ábrányi-Balogh P;Brandão-Neto J;Carbery A;Davison G;Dias A;Downes TD;Dunnett L;Fairhead M;Firth JD;Jones SP;Keeley A;Keserü GM;Klein HF;Martin MP;Noble MEM;O'Brien P;Powell A;Reddi RN;Skyner R;Snee M;Waring MJ;Wild C;London N;von Delft F;Walsh MA
通讯作者：
Walsh MA
影响因子：
14.8
作者：
Akcay, Gizem;Belmonte, Matthew A.;Su, Qibin
通讯作者：
Su, Qibin
影响因子：
4.7
作者：
Du, Huang-Chi;Bangs, Madison C.;Matzuk, Martin M.
通讯作者：
Matzuk, Martin M.
影响因子：
--
作者：
Faver, John C.;Riehle, Kevin;Matzuk, Martin M.
通讯作者：
Matzuk, Martin M.