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Combined Antibodies Evusheld against the SARS-CoV-2 Omicron Variants BA.1.1 and BA.5: Immune Escape Mechanism from Molecular Simulation.
Zhang, Jianwen; Cong, Yalong; Duan, Lili; Zhang, John Z H.
Afiliación
  • Zhang J; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • Cong Y; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • Duan L; School of Physics and Electronics, Shandong Normal University, Jinan 250014, China.
  • Zhang JZH; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
J Chem Inf Model ; 63(16): 5297-5308, 2023 08 28.
Article en En | MEDLINE | ID: mdl-37586058
The Omicron lineage of SARS-CoV-2, which was first reported in November 2021, has spread globally and become dominant, splitting into several sublineages. Experiments have shown that Omicron lineage has escaped or reduced the activity of existing monoclonal antibodies, but the origin of escape mechanism caused by mutation is still unknown. This work uses molecular dynamics and umbrella sampling methods to reveal the escape mechanism of BA.1.1 to monoclonal antibody (mAb) Tixagevimab (AZD1061) and BA.5 to mAb Cilgavimab (AZD8895), both mAbs were combined to form antibody cocktail, Evusheld (AZD7442). The binding free energy of BA.1.1-AZD1061 and BA.5-AZD8895 has been severely reduced due to multiple-site mutated Omicron variants. Our results show that the two Omicron variants, which introduce a substantial number of positively charged residues, can weaken the electrostatic attraction between the receptor binding domain (RBD) and AZD7442, thus leading to a decrease in affinity. Additionally, using umbrella sampling along dissociation pathway, we found that the two Omicron variants severely impaired the interaction between the RBD of SARS-CoV-2's spike glycoprotein (S protein) and complementary determining regions (CDRs) of mAbs, especially in CDR3H. Although mAbs AZD8895 and AZD1061 are knocked out by BA.5 and BA.1.1, respectively, our results confirm that the antibody cocktail AZD7442 retains activity against BA.1.1 and BA.5 because another antibody is still on guard. The study provides theoretical insights for mAbs interacting with BA.1.1 and BA.5 from both energetic and dynamic perspectives, and we hope this will help in developing new monoclonals and combinations to protect those unable to mount adequate vaccine responses.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Evasión Inmune / COVID-19 Límite: Humans Idioma: En Revista: J Chem Inf Model Asunto de la revista: INFORMATICA MEDICA / QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Evasión Inmune / COVID-19 Límite: Humans Idioma: En Revista: J Chem Inf Model Asunto de la revista: INFORMATICA MEDICA / QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos