Structure–Function Analysis of Resistance to Bamlanivimab by SARS-CoV-2 Variants Kappa, Delta, and Lambda,Journal of Chemical Information and Modeling

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Structure–Function Analysis of Resistance to Bamlanivimab by SARS-CoV-2 Variants Kappa, Delta, and Lambda
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2021-10-14 , DOI: 10.1021/acs.jcim.1c01058
Shufeng Liu ₁ , Tien Huynh ₂ , Charles B Stauft ₁ , Tony T Wang ₁ , Binquan Luan ₂

Affiliation

The newly emerging Kappa, Delta, and Lambda SARS-CoV-2 variants are worrisome, characterized with the double mutations E484Q/L452R, T478K/L452R, and F490S/L452Q, respectively, in their receptor binding domains (RBDs) of the spike proteins. As revealed in crystal structures, most of these residues (e.g., 452 and 484 in RBDs) are not in direct contact with interfacial residues in the angiotensin-converting enzyme 2 (ACE2). This suggests that albeit there are some possibly nonlocal effects, these mutations might not significantly affect RBD’s binding with ACE2, which is an important step for viral entry into host cells. Thus, without knowing the molecular mechanism, these successful mutations (from the point of view of SARS-CoV-2) may be hypothesized to evade human antibodies. Using all-atom molecular dynamics (MD) simulation, here, we show that the E484Q/L452R mutations significantly reduce the binding affinity between the RBD of the Kappa variant and the antibody LY-CoV555 (also named as Bamlanivimab), which was efficacious for neutralizing the wild-type SARS-CoV-2. To verify simulation results, we further carried out experiments with both pseudovirions- and live virus-based neutralization assays and demonstrated that LY-CoV555 completely lost neutralizing activity against the L452R/E484Q mutant. Similarly, we show that mutations in the Delta and Lambda variants can also destabilize the RBD’s binding with LY-CoV555. With the revealed molecular mechanism on how these variants evade LY-CoV555, we expect that more specific therapeutic antibodies can be accordingly designed and/or a precise mixing of antibodies can be achieved as a cocktail treatment for patients infected with these variants.

中文翻译：

SARS-CoV-2 变异体 Kappa、Delta 和 Lambda 对 Bamlanivimab 耐药性的结构-功能分析

新出现的 Kappa、Delta 和 Lambda SARS-CoV-2 变体令人担忧，其刺突蛋白受体结合域 (RBD) 中分别存在双突变 E484Q/L452R、T478K/L452R 和 F490S/L452Q 。正如晶体结构所示，大多数残基（例如 RBD 中的 452 和 484）不与血管紧张素转换酶 2 (ACE2) 中的界面残基直接接触。这表明尽管可能存在一些非局部效应，但这些突变可能不会显着影响 RBD 与 ACE2 的结合，而 ACE2 是病毒进入宿主细胞的重要步骤。因此，在不了解分子机制的情况下，这些成功的突变（从 SARS-CoV-2 的角度来看）可能被假设为逃避人类抗体。通过全原子分子动力学 (MD) 模拟，我们发现 E484Q/L452R 突变显着降低了 Kappa 变体的 RBD 与抗体 LY-CoV555（也称为 Bamlanivimab）之间的结合亲和力，这对于中和野生型 SARS-CoV-2。为了验证模拟结果，我们进一步进行了基于伪病毒颗粒和活病毒的中和测定实验，并证明 LY-CoV555 完全失去了对 L452R/E484Q 突变体的中和活性。同样，我们发现 Delta 和 Lambda 变体的突变也会破坏 RBD 与 LY-CoV555 结合的稳定性。随着这些变体如何逃避 LY-CoV555 的分子机制被揭示，我们期望可以相应地设计更特异性的治疗抗体和/或可以实现抗体的精确混合，作为感染这些变体的患者的鸡尾酒疗法。

更新日期：2021-10-25

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