SARS-CoV-2 Spike Mutations, L452R, T478K, E484Q and P681R, in the Second Wave of COVID-19 in Maharashtra, India

Abstract

As the global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic expands, genomic epidemiology and whole genome sequencing are being used to investigate its transmission and evolution. Against the backdrop of the global emergence of “variants of concern” (VOCs) during December 2020 and an upsurge in a state in the western part of India since January 2021, whole genome sequencing and analysis of spike protein mutations using sequence and structural approaches were undertaken to identify possible new variants and gauge the fitness of the current circulating strains. Phylogenetic analysis revealed that newly identified lineages B.1.617.1 and B.1.617.2 were predominantly circulating. The signature mutations possessed by these strains were L452R, T478K, E484Q, D614G and P681R in the spike protein, including within the receptor-binding domain (RBD). Of these, the mutations at residue positions 452, 484 and 681 have been reported in other globally circulating lineages. The structural analysis of RBD mutations L452R, T478K and E484Q revealed that these may possibly result in increased ACE2 binding while P681R in the furin cleavage site could increase the rate of S1-S2 cleavage, resulting in better transmissibility. The two RBD mutations, L452R and E484Q, indicated decreased binding to select monoclonal antibodies (mAbs) and may affect their neutralization potential. Further in vitro/in vivo studies would help confirm the phenotypic changes of the mutant strains. Overall, the study revealed that the newly emerged variants were responsible for the second wave of COVID-19 in Maharashtra. Lineage B.1.617.2 has been designated as a VOC delta and B.1.617.1 as a variant of interest kappa, and they are being widely reported in the rest of the country as well as globally. Continuous monitoring of these and emerging variants in India is essential.

Molecular Dynamics Simulation Study of the Interaction between Human Angiotensin Converting Enzyme 2 and Spike Protein Receptor Binding Domain of the SARS-CoV-2 B.1.617 Variant

“…In support of our results, Cherian and colleagues reported that the L452R mutation, and E484Q, could reduce intramolecular and intermolecular interactions and disrupts an electrostatic bond with Lys31 of hACE2 [27]. A change from a hydrophobic leucine on the protein surface to arginine (L452R) also increases its interactions with water molecules that could further stabilize the protein.…”

“…Thus, conformational changes in the RBD, induced by the E484Q mutation, could impact the stability of the hACE2 binding surface. Furthermore, Glu484 is as an important antibody escape site of SARS-CoV-2 and mutations at this location could impact the binding and neutralization by antibodies [27]. Studies have also demonstrated that the E484Q mutation could reduce the neutralization by plasma and antibodies by 10-fold [28].…”

SARS-CoV-2 Delta Variant Pathogenesis and Host Response in Syrian Hamsters

“…As of 10 August 2021, the Delta variant has been reported in 142 countries [1]. The characteristic mutations reported in the spike gene of the B.1.617 lineage are D111D, L452R, D614G, P618R, and ±E484Q [3]. These mutations suggest increased ACE2 binding, transmissibility, and escape of neutralization [3][4][5][6].…”

“…The characteristic mutations reported in the spike gene of the B.1.617 lineage are D111D, L452R, D614G, P618R, and ±E484Q [3]. These mutations suggest increased ACE2 binding, transmissibility, and escape of neutralization [3][4][5][6]. Available evidence suggests increased transmissibility, secondary attack rate, hospitalization risk, and immune escape by the Delta variant [1,7].…”

The Delta SARS-CoV-2 variant has a higher viral load than the Beta and the historical variants in nasopharyngeal samples from newly diagnosed COVID-19 patients

“…Indeed, it has been shown that the L452R mutation leads to increased infectivity, though slightly lower than with the N501Y mutation, compared to historical lineages 9 . Moreover, the L452R and the T478K possibly increase ACE2 binding and the stabilization of the ACE2-RBD complex and the P681R, present in the furin cleavage site, could enhance the transmissibility of the virus by its action on the S1-S2 cleavage 10 . These mutations confer equally to the virus a resistance to neutralizing monoclonal antibodies by disrupting their binding ability to the RBD spike 10 and could play a role in vaccine escape, which could explain its worldwide predominance.…”