SARS-CoV-2 VOCs, Mutational diversity and clinical outcome: Are they modulating drug efficacy by altered binding strength?

Saifi, Sheeba; Ravi, Varsha; Sharma, Sparsh; Swaminathan, Aparna; Chauhan, Nar Singh; Pandey, Rajesh

doi:10.1016/j.ygeno.2022.110466

Cited by 23 publications

(17 citation statements)

References 59 publications

(59 reference statements)

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“…Weisblum et al found that K444R/Q/N occurs after exposure to convalescent plasma [55]. Among largely diversified VOCs such as Delta, S:K444N was associated with reduced remdesivir binding and increased mortality [56].…”

Section: S:k444xmentioning

confidence: 99%

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Focosi¹,

Quiroga

McConnell

et al. 2022

Preprint

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The first 2 years of the COVID-19 pandemic were mainly characterized by convergent evolution of mutations of SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 across different variants of concern (Alpha, Beta, Gamma, and Delta). Since Spring 2022 and the third year of the pandemic, with the advent of Omicron and its sublineages, convergent evolution has led to the observation of different lineages acquiring an additional group of mutations at different amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, and S494. Mutations at these residues have become increasingly prevalent during Summer and Autumn 2022, with combinations showing increased fitness. The most likely reason for this convergence is the selective pressure exerted by previous infection- or vaccine-elicited immunity. Such accelerated evolution has caused failure of all anti-Spike monoclonal antibodies, including bebtelovimab and cilgavimab. While we are learning how fast coronaviruses can mutate and recombine, we should reconsider opportunities for economically sustainable escape-proof combination therapies, and reevaluate the potential for polyclonal therapies (such as COVID19 convalescent plasma) in immunocompromised patients.

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Section: S:k444xmentioning

confidence: 99%

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Focosi¹,

Quiroga

McConnell

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Additionally, in previous studies, it has been shown that Q493R in the RBD spike is significantly associated with Omicron disease severity in patients. Docking studies of Remdesivir with R493 mutant viral protein demonstrated a reduction in the binding strength of Remdesivir to mutant Spike proteins [ 60 ]. As for the E484 residue mutated to A484, the E484 in the spike WT of the RBD forms contact with K31 in ACE2 WT.…”

Section: Resultsmentioning

confidence: 99%

Computational modeling of the effect of five mutations on the structure of the ACE2 receptor and their correlation with infectivity and virulence of some emerged variants of SARS-CoV-2 suggests mechanisms of binding affinity dysregulation

Rodríguez

González²,

Arboleda-Bustos³

et al. 2022

Chemico-Biological Interactions

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“…The 440-position found at a loop near the binding interface [ 65 ] causes a change of charge and has been shown to massively increase the interaction energy of the RBD with ACE2 [ 60 ], as well as an increased ability to escape neutralising antibodies [ 68 ]. It is also associated with an increased mortality [ 69 ]. Mutations including Asn-to-Lys (as seen in BA.1, BA.1.1, BA.2, group 5, XBB, BJ.1, BA.2.12.1, BA.2.75.4, BA.2.75.5, BA.2.75.7, BF.7, and BQ.1.1) cause a change of charge, leading to a positively charged interface.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations including Asn-to-Lys (as seen in BA.1, BA.1.1, BA.2, group 5, XBB, BJ.1, BA.2.12.1, BA.2.75.4, BA.2.75.5, BA.2.75.7, BF.7, and BQ.1.1) cause a change of charge, leading to a positively charged interface. Previous studies reported that mutation of residue K444N (BU.1, BW.1, group 5, XBB, and BJ.1) was associated with increased mortality [ 69 ]. Mutation at residue G446S shows polarity changes, although it has been shown to decrease ACE2 binding [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…A mutation in residue at position Q493 to Arg (BA.1, BA.1.1, BA.2, group 1, BA.2.75.4, and BA.2.12.1) disrupts the interaction and creates a salt bridge with ACE2-R35, conferring additional strength [ 58 , 59 ]. Interestingly, the mutation to Arg is the most conserved change at this residue and it is mainly associated with Omicron variant mortality [ 69 ]. In addition, G496 can form a direct contact with ACE2 [ 65 ] and its mutation G496S (BA.1 and BA.1.1) leading to a formation of hydrogen bonds with ACE2-D38 due to the change in polarity and an increase in the binding [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

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Deep Structural Analysis of Myriads of Omicron Sub-Variants Revealed Hotspot for Vaccine Escape Immunity

et al. 2023

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The emergence of the Omicron variant has reinforced the importance of continued SARS-CoV-2 evolution and its possible impact on vaccine effectiveness. Specifically, mutations in the receptor-binding domain (RBD) are critical to comprehend the flexibility and dynamicity of the viral interaction with the human agniotensin-converting enzyme 2 (hACE2) receptor. To this end, we have applied a string of deep structural and genetic analysis tools to map the substitution patterns in the S protein of major Omicron sub-variants (n = 51) with a primary focus on the RBD mutations. This head-to-head comparison of Omicron sub-variants revealed multiple simultaneous mutations that are attributed to antibody escape, and increased affinity and binding to hACE2. Our deep mapping of the substitution matrix indicated a high level of diversity at the N-terminal and RBD domains compared with other regions of the S protein, highlighting the importance of these two domains in a matched vaccination approach. Structural mapping identified highly variable mutations in the up confirmation of the S protein and at sites that critically define the function of the S protein in the virus pathobiology. These substitutional trends offer support in tracking mutations along the evolutionary trajectories of SAR-CoV-2. Collectively, the findings highlight critical areas of mutations across the major Omicron sub-variants and propose several hotspots in the S proteins of SARS-CoV-2 sub-variants to train the future design and development of COVID-19 vaccines.

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SARS-CoV-2 VOCs, Mutational diversity and clinical outcome: Are they modulating drug efficacy by altered binding strength?

Cited by 23 publications

References 59 publications

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Computational modeling of the effect of five mutations on the structure of the ACE2 receptor and their correlation with infectivity and virulence of some emerged variants of SARS-CoV-2 suggests mechanisms of binding affinity dysregulation

Deep Structural Analysis of Myriads of Omicron Sub-Variants Revealed Hotspot for Vaccine Escape Immunity

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