Targeting an evolutionarily conserved "E-L-L" motif in spike protein to identify a small molecule fusion inhibitor against SARS-CoV-2.
Targeting an evolutionarily conserved "E-L-L" motif in spike protein to identify a small molecule fusion inhibitor against SARS-CoV-2.
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DOI：
10.1093/pnasnexus/pgac198
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发表时间：
2022-11
期刊：
影响因子：
--
通讯作者：
Mondal, Arindam
中科院分区：
文献类型：
--
作者：
Jana, Indrani Das;Bhattacharya, Prabuddha;Mayilsamy, Karthick;Banerjee, Saptarshi;Bhattacharje, Gourab;Das, Sayan;Aditya, Seemanti;Ghosh, Anandita;McGill, Andrew R.;Srikrishnan, Syamanthak;Das, Amit Kumar;Basak, Amit;Mohapatra, Shyam S.;Chandran, Bala;Bhimsaria, Devesh;Mohapatra, Subhra;Roy, Arunava;Mondal, Arindam
随着SARS-CoV-2的新变种继续对全球人类健康和经济构成重大威胁，识别新的可药物抗病毒靶标是维持生存的关键。在这里，我们发现了一个进化上保守的“Ex3Lx6L”(“E-L-L”)基序，存在于所有人和非人类冠状病毒尖峰蛋白(S)的HR2结构域中，它在稳定融合后的六螺旋束(6-HB)结构从而融合介导的病毒进入中起着至关重要的作用。该基序中的突变降低了S蛋白的融合性，而不影响其稳定性或膜定位。我们发现FDA批准的药物泊沙康唑能与E-L-L基序结合，并阻止6-Hb的形成，从而有效地抑制SARS-CoV-2在细胞内的感染。泊沙康唑在阻断S蛋白介导的病毒侵入方面表现出高效的作用，但“E-L-L”基序的突变使该蛋白对药物产生完全抗药性，从而确立了其对该基序的特异性。我们的数据表明泊沙康唑通过特异性地抑制膜融合和病毒基因组向宿主细胞的释放来限制感染的早期阶段，并且对SARS-CoV-2的所有主要变种都同样有效，包括Beta、Kappa、Delta和Omicron。综上所述，我们认为这个保守的“E-L-L”基序是开发针对SARS-CoV-2的预防和治疗干预措施的理想靶点。
As newer variants of SARS-CoV-2 continue to pose major threats to global human health and economy, identifying novel druggable antiviral targets is the key toward sustenance. Here, we identify an evolutionarily conserved “Ex3Lx6L” (“E-L-L”) motif present within the HR2 domain of all human and nonhuman coronavirus spike (S) proteins that play a crucial role in stabilizing its postfusion six-helix bundle (6-HB) structure and thus, fusion-mediated viral entry. Mutations within this motif reduce the fusogenicity of the S protein without affecting its stability or membrane localization. We found that posaconazole, an FDA-approved drug, binds to this “E-L-L” motif and impedes the formation of 6-HB, thus effectively inhibiting SARS-CoV-2 infection in cells. While posaconazole exhibits high efficacy in blocking S protein-mediated viral entry, mutations within the “E-L-L” motif rendered the protein completely resistant to the drug, establishing its specificity toward this motif. Our data demonstrate that posaconazole restricts early stages of infection through specific inhibition of membrane fusion and viral genome release into the host cell and is equally effective toward all major variants of concerns of SARS-CoV-2, including Beta, Kappa, Delta, and Omicron. Together, we show that this conserved essential “E-L-L” motif is an ideal target for the development of prophylactic and therapeutic interventions against SARS-CoV-2.
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影响因子：
4.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
64.8
作者：
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通讯作者：
Gupta RK