An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants.
An ACE2 Triple Decoy that neutralizes SARS-CoV-2 shows enhanced affinity for virus variants.
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DOI：
10.1038/s41598-021-91809-9
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发表时间：
2021-06-17
影响因子：
4.6
通讯作者：
Soon-Shiong P
中科院分区：
文献类型：
--
作者：
Tanaka S;Nelson G;Olson CA;Buzko O;Higashide W;Shin A;Gonzalez M;Taft J;Patel R;Buta S;Richardson A;Bogunovic D;Spilman P;Niazi K;Rabizadeh S;Soon-Shiong P
取代第一波毒株的SARS-CoV-2变体由于其逃避预先存在的体液保护的潜在能力而构成更大的威胁。与内源性ACE 2竞争结合SARS-CoV-2刺突受体结合域（S RBD）并抑制感染的血管紧张素转换酶2（ACE 2）诱饵可能提供对变体具有持续疗效的治疗选择。在这里，我们使用分子动力学（MD）模拟来预测ACE 2序列取代，可能会增加其对S RBD的亲和力，并在体外筛选候选ACE 2诱饵。具有增强的S RBD亲和力的前导ACE 2（T27 Y/H34 A）-IgG 1FC融合蛋白显示出比野生型ACE 2更强的活SARS-CoV-2病毒中和能力。使用MD模拟来预测S RBD变体突变对诱饵亲和力的影响，然后通过测试ACE 2三重诱饵来证实，所述ACE 2三重诱饵包括针对突变的S RBD的额外的酶活性失活H374 N取代。ACE 2 Triple Decoy对突变的S RBD保持高亲和力，对S RBD N501 Y或L452 R表现出增强的亲和力，并且对具有E484 K和N501 Y突变的S RBD具有最高的亲和力，使其成为预防或治疗SARS-CoV-2感染的可行治疗选择，对变体具有高可能性的疗效。
The SARS-CoV-2 variants replacing the first wave strain pose an increased threat by their potential ability to escape pre-existing humoral protection. An angiotensin converting enzyme 2 (ACE2) decoy that competes with endogenous ACE2 for binding of the SARS-CoV-2 spike receptor binding domain (S RBD) and inhibits infection may offer a therapeutic option with sustained efficacy against variants. Here, we used Molecular Dynamics (MD) simulation to predict ACE2 sequence substitutions that might increase its affinity for S RBD and screened candidate ACE2 decoys in vitro. The lead ACE2(T27Y/H34A)-IgG1FC fusion protein with enhanced S RBD affinity shows greater live SARS-CoV-2 virus neutralization capability than wild type ACE2. MD simulation was used to predict the effects of S RBD variant mutations on decoy affinity that was then confirmed by testing of an ACE2 Triple Decoy that included an additional enzyme activity-deactivating H374N substitution against mutated S RBD. The ACE2 Triple Decoy maintains high affinity for mutated S RBD, displays enhanced affinity for S RBD N501Y or L452R, and has the highest affinity for S RBD with both E484K and N501Y mutations, making it a viable therapeutic option for the prevention or treatment of SARS-CoV-2 infection with a high likelihood of efficacy against variants.
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影响因子：
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