A molecularly engineered, broad-spectrum anti-coronavirus lectin inhibits SARS-CoV-2 and MERS-CoV infection in vivo.
A molecularly engineered, broad-spectrum anti-coronavirus lectin inhibits SARS-CoV-2 and MERS-CoV infection in vivo.
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DOI：
10.1016/j.xcrm.2022.100774
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发表时间：
2022-10-18
影响因子：
14.3
通讯作者：
Markovitz, David M.
中科院分区：
文献类型：
--
作者：
Chan, Jasper Fuk-Woo;Oh, Yoo Jin;Yuan, Shuofeng;Chu, Hin;Yeung, Man-Lung;Canena, Daniel;Chan, Chris Chung-Sing;Poon, Vincent Kwok-Man;Chan, Chris Chun-Yiu;Zhang, Anna Jinxia;Cai, Jian-Piao;Ye, Zi-Wei;Wen, Lei;Yuen, Terrence Tsz-Tai;Chik, Kenn Ka-Heng;Shuai, Huiping;Wang, Yixin;Hou, Yuxin;Luo, Cuiting;Chan, Wan-Mui;Qin, Zhenzhi;Sit, Ko-Yung;Au, Wing-Kuk;Legendre, Maureen;Zhu, Rong;Hain, Lisa;Seferovic, Hannah;Tampe, Robert;To, Kelvin Kai-Wang;Chan, Kwok-Hung;Thomas, Dafydd Gareth;Klausberger, Miriam;Xu, Cheng;Moon, James J.;Stadlmann, Johannes;Penninger, Josef M.;Oostenbrink, Chris;Hinterdorfer, Peter;Yuen, Kwok-Yung;Markovitz, David M.
可以设计针对保守病毒成分的“泛冠状病毒”抗病毒药物。在这里，我们展示了合理设计的H84T-香蕉凝集素(H84T-BanLec)，它特异性地识别病毒蛋白上发现的高甘露糖，但很少在健康的人类细胞上发现，在纳摩尔浓度下有效地抑制中东呼吸综合征冠状病毒(MERS-CoV)、严重急性呼吸综合征冠状病毒2(SARS-CoV-2)(包括Omicron)和其他人类致病冠状病毒。H84T-BanLec在体内对MERS-CoV和SARS-CoV-2感染具有保护作用。重要的是，H84T-BanLec鼻腔给药和腹膜内给药同样有效。机制分析表明，H84T-BanLec针对病毒入侵。高速原子力显微镜描绘了H84T-BanLec二聚体与SARS-CoV-2尖峰三聚体的实时多分子结合。单分子力谱显示H84T-BanLec与多个SARS-CoV-2尖峰甘露糖高亲和力结合，H84T-BanLec与SARS-CoV-2尖峰竞争结合细胞ACE2。建模实验确定了H84T-BanLec识别的穗状物中明显的高甘露糖聚糖。SPEK上的多个H84T-BanLec结合位点可能是该药物化合物具有广谱抗病毒活性和缺乏抗药性突变体的原因。H84T-BanLec通过抑制病毒进入抑制人类致病冠状病毒H84T-BanLec在体内保护MERS-CoV和SARS-CoV-2感染H84T-BanLec高亲和力结合多个SARS-CoV-2刺激性高甘露糖位点这一独特机制可能解释了H84T-BanLec的广谱活性Chan等人。研究H84T-BanLec对人致病冠状病毒的抗病毒活性及其机制。H84T-BanLec通过抑制病毒进入而具有泛冠状病毒抗病毒活性，并对体内MERS-CoV和SARS-CoV-2感染具有保护作用。H84T-BanLec与穗部多个高甘露糖结合可能是其缺乏抗性突变体的原因。
“Pan-coronavirus” antivirals targeting conserved viral components can be designed. Here, we show that the rationally engineered H84T-banana lectin (H84T-BanLec), which specifically recognizes high mannose found on viral proteins but seldom on healthy human cells, potently inhibits Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (including Omicron), and other human-pathogenic coronaviruses at nanomolar concentrations. H84T-BanLec protects against MERS-CoV and SARS-CoV-2 infection in vivo. Importantly, intranasally and intraperitoneally administered H84T-BanLec are comparably effective. Mechanistic assays show that H84T-BanLec targets virus entry. High-speed atomic force microscopy depicts real-time multimolecular associations of H84T-BanLec dimers with the SARS-CoV-2 spike trimer. Single-molecule force spectroscopy demonstrates binding of H84T-BanLec to multiple SARS-CoV-2 spike mannose sites with high affinity and that H84T-BanLec competes with SARS-CoV-2 spike for binding to cellular ACE2. Modeling experiments identify distinct high-mannose glycans in spike recognized by H84T-BanLec. The multiple H84T-BanLec binding sites on spike likely account for the drug compound’s broad-spectrum antiviral activity and the lack of resistant mutants. H84T-BanLec inhibits human-pathogenic coronaviruses through inhibition of viral entry H84T-BanLec protects against MERS-CoV and SARS-CoV-2 infections in vivo H84T-BanLec binds to multiple SARS-CoV-2 spike high-mannose sites with high affinity This unique mechanism likely accounts for H84T-BanLec’s broad-spectrum activity Chan et al. investigate the antiviral activity and mechanism of H84T-BanLec against human-pathogenic coronaviruses. H84T-BanLec possesses pan-coronaviral antiviral activity through inhibition of viral entry and protects against MERS-CoV and SARS-CoV-2 infections in vivo. Binding of H84T-BanLec to multiple high-mannose glycans in spike likely accounts for its lack of resistant mutants.
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影响因子：
13.6
作者：
Farkash, Evan A.;Wilson, Allecia M.;Jentzen, Jeffrey M.
通讯作者：
Jentzen, Jeffrey M.
超越屏蔽：聚糖在SARS-COV-2尖峰蛋白中的作用。
影响因子：
18.2
作者：
Casalino L;Gaieb Z;Goldsmith JA;Hjorth CK;Dommer AC;Harbison AM;Fogarty CA;Barros EP;Taylor BC;McLellan JS;Fadda E;Amaro RE
通讯作者：
Amaro RE
影响因子：
13.2
作者：
Chan, Jasper Fuk-Woo;Kok, Kin-Hang;Yuen, Kwok-Yung
通讯作者：
Yuen, Kwok-Yung
影响因子：
168.9
作者：
Chan, Jasper Fuk-Woo;Yuan, Shuofeng;Yuen, Kwok-Yung
通讯作者：
Yuen, Kwok-Yung
影响因子：
6.4
作者：
Chan, Jasper Fuk-Woo;Chan, Kwok-Hung;Yuen, Kwok-Yung
通讯作者：
Yuen, Kwok-Yung