Genetic variants in TMPRSS2 and Structure of SARS-CoV-2 spike glycoprotein and TMPRSS2 complex

Vishnubhotla, Ravikanth; Vankadari, Naveen; Ketavarapu, Vijayasarathy; Amanchy, Ramars; Avanthi, Steffie; Govardhan, Bale; Reddy, Duvvur Nageshwar; Sasikala, Mitnala

doi:10.1101/2020.06.30.179663

Cited by 17 publications

(16 citation statements)

References 36 publications

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“…Two different in silico investigations predicted the impact of this variant in viral entry into the host cell. One suggested that this variant produces a largest de novo pocket protein, which might affect the TMPRSS2 structure [ 72 ] and the other reported decreased stability of the protein in the presence of this variant [ 73 ]. However, Vargas-Alarcón and colleagues (2020) have illustrated no possible effect of this variant on the TMPRSS2 post-translational modifications.…”

Section: Discussionmentioning

confidence: 99%

ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: A time to implement precision medicine against COVID-19

Al-Mulla¹,

Mohammad²,

Madhoun³

et al. 2021

Heliyon

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The severity of the new COVID-19 pandemic caused by the SARS-CoV-2 virus is strikingly variable in different global populations. SARS-CoV-2 uses ACE2 as a cell receptor, TMPRSS2 protease, and FURIN peptidase to invade human cells. Here, we investigated 1,378 whole-exome sequences of individuals from the Middle Eastern populations (Kuwait, Qatar, and Iran) to explore natural variations in the ACE2, TMPRSS2, and FURIN genes. We identified two activating variants (K26R and N720D) in the ACE2 gene that are more common in Europeans than in the Middle Eastern, East Asian, and African populations. We postulate that K26R can activate ACE2 and facilitate binding to S-protein RBD while N720D enhances TMPRSS2 cutting and, ultimately, viral entry. We also detected deleterious variants in FURIN that are frequent in the Middle Eastern but not in the European populations. This study highlights specific genetic variations in the ACE2 and FURIN genes that may explain SARS-CoV-2 clinical disparity. We showed structural evidence of the functionality of these activating variants that increase the SARS-CoV-2 aggressiveness. Finally, our data illustrate a significant correlation between ACE2 variants identified in people from Middle Eastern origins that can be further explored to explain the variation in COVID-19 infection and mortality rates globally.

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Section: Discussionmentioning

confidence: 99%

ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: A time to implement precision medicine against COVID-19

Al-Mulla¹,

Mohammad²,

Madhoun³

et al. 2021

Heliyon

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“…While D614G was hypothesized to increase SARS-CoV-2 infectivity by influencing the dynamics of the spatially proximal fusion peptide [ 13 ], D839Y, which itself falls within functional fusogenic element of Spike[ 2 , 13 ], could also have shaped this motif towards a better fitted fusion of SARS-CoV-2 with human cells. Also, recent data based on computational modeling suggested that mutations in Spike D839 may strengthen the interaction between the virus and human T cells potentially influencing host inflammatory responses [in particular, when replacing the aspartic acid (D) to an aromatic tyrosine (Y)] [ 19 ], and may influence Spike cleavage by host proteases during SARS-CoV-2 fusion activation and entry [ 20 ]. Nevertheless, these clues about the potential impact of this mutation on SARS-CoV-2 transmissibility/pathogenicity require evidence through experimental validation to verify or rule out the fitness advantage hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…The fusion mechanism is also pointed out as an important target for the development of specific drugs against coronavirus, since it is expectedly less mutable than the surface-exposed and immunogenic RBD [ 2 , 18 ]. The Spike amino acid 839, within the fusion peptide or proximal regions (there is still no consensus on their precise location) [ 2 ], is being highlighted due to its potential specific host-interacting role in Spike cleavage for SARS-CoV-2 fusion activation and/or in the induction of host inflammatory responses [ 13 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Massive dissemination of a SARS-CoV-2 Spike Y839 variant in Portugal

Borges

Isidro

Martins

et al. 2020

Emerging Microbes & Infections

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Genomic surveillance of SARS-CoV-2 was rapidly implemented in Portugal by the National Institute of Health in collaboration with a nationwide consortium of >50 hospitals/laboratories. Here, we track the geotemporal spread of a SARS-CoV-2 variant with a mutation (D839Y) in a potential host-interacting region involving the Spike fusion peptide, which is a target motif of anti-viral drugs that plays a key role in SARS-CoV-2 infectivity. The Spike Y839 variant was most likely imported from Italy in mid-late February and massively disseminated in Portugal during the early epidemic, becoming prevalent in the Northern and Central regions of Portugal where it represented 22% and 59% of the sampled genomes, respectively, by 30 April. Based on our high sequencing sampling during the early epidemics [15.5% (1275/8251) and 6.0% (1500/24987) of all confirmed cases until the end of March and April, respectively], we estimate that, between 14 March and 9 April (covering the epidemic exponential phase) the relative frequency of the Spike Y839 variant increased at a rate of 12.1% (6.1%–18.2%, CI 95%) every three days, being potentially associated with 24.8% (20.8–29.7%, CI 95%; 3177–4542 cases, CI 95%) of all COVID-19 cases in Portugal during this period. Our data supports population/epidemiological (founder) effects contributing to the Y839 variant superspread. The potential existence of selective advantage is also discussed, although experimental validation is required. Despite huge differences in genome sampling worldwide, SARS-CoV-2 Spike D839Y has been detected in 13 countries in four continents, supporting the need for close surveillance and functional assays of Spike variants.

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“…The whole structure of this serine protease enzyme measures 42 × 24 Å and consists of an N-terminal activation domain and a C-terminal catalytic domain. Vishnubhotla et al ( 2020 ) have mapped the active site of the enzyme and noticed the highly conserved nature of amino acid residues His296, Ser441, Lys432, Trp461 and Gln438 present in this site.…”

Section: Drug Targetsmentioning

confidence: 99%

Molecular targets and system biology approaches for drug repurposing against SARS-CoV-2

2020

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Background COVID-19, a pandemic declared by WHO, has infected about 39.5 million and killed about 1.1 million people throughout the world. There is the urgent need of more studies to identify the novel drug targets and the drug candidates against it to handle the situation. Main body To virtually screen various drugs against SARS-CoV-2, the scientists need the detail information about the various drug targets identified till date. The present review provides the information about almost all the drug targets, including structural and non-structural proteins of virus as well as host cell surface receptors, that can be used for virtual screening of drugs. Moreover, this review also focuses on the different network analysis tools that have been used for the identification of new drug targets and candidate repurposable drugs against SARS-CoV-2. Conclusion This review provides important insights of various drug targets and the network analysis tools to young bioinformaticians and will help in creating pace to the drug repurposing strategy for COVID-19 disease.

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Genetic variants in TMPRSS2 and Structure of SARS-CoV-2 spike glycoprotein and TMPRSS2 complex

Cited by 17 publications

References 36 publications

ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: A time to implement precision medicine against COVID-19

ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: A time to implement precision medicine against COVID-19

Massive dissemination of a SARS-CoV-2 Spike Y839 variant in Portugal

Molecular targets and system biology approaches for drug repurposing against SARS-CoV-2

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