Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation

Fraser, Bryan J.; Beldar, Serap; Seitova, Almagul; Hutchinson, A.; Mannar, Dhiraj; Li, Yanjun; Kwon, Daniel H.; Tan, Ruiyan; Wilson, Ryan P.; Leopold, Karoline; Subramaniam, Sriram; Halabelian, L.; Arrowsmith, C.H.; Bénard, François

doi:10.1038/s41589-022-01059-7

Cited by 121 publications

(152 citation statements)

References 56 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…Many studies have shown that furin and TMPRSS2 cleave SARS-CoV-2 S protein at the S1/S2 and S2’ sites, respectively ( Fig. 10 A), although alternative furin and TMPRSS2 cleavages have been reported ( 20 , 21 , 59 , 60 ). Given the finding of intracellular TMPRSS2 activation, we tested if TMPRSS2 could cleave SARS-CoV-2 S protein intracellularly.…”

Section: Resultsmentioning

confidence: 99%

Transmembrane serine protease TMPRSS2 implicated in SARS-CoV-2 infection is autoactivated intracellularly and requires N-glycosylation for regulation

Zhang

Sun

et al. 2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 99%

Transmembrane serine protease TMPRSS2 implicated in SARS-CoV-2 infection is autoactivated intracellularly and requires N-glycosylation for regulation

Zhang

Sun

et al. 2022

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…The 3D structures of the selected target proteins, SARS-CoV-2 RdRp (PDB ID:6M71-Chain A) (Gao et al 2020 Jan 1 ), SARS-CoV-2 M pro (PDB ID: 6LU7-Chain A) (Jin et al 2020 ), also spike receptor in complex with human ACE2 receptor (PDB ID: 6M0J) (Lan et al 2020 May) and the TMPRSS2 target (PDB ID: 7MEQ) which plays a crucial role in SARS-COV-2 (Fraser et al 2022 Jun) were retrieved from the protein data bank ( www.rcsb.org ) (Burley et al 2021 ).…”

Section: Methodsmentioning

confidence: 99%

In silico investigation of the therapeutic and prophylactic potential of medicinal substances bearing guanidine moieties against COVID-19

Esam

Akhavan

Lotfi³

et al. 2022

Chem. Pap.

View full text Add to dashboard Cite

The current viral pandemic, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), creates health, mental, economic, and other serious challenges that are better to say global crisis. Despite the existence of successful vaccines, the possible mutations which can lead to the born of novel and possibly more dangerous variants of the virus as well as the absence of definitive treatment for this potentially fatal multiple-organ infection in critically ill patients make us keep searching. Theoretically targeting human and viral receptors and enzymes via molecular docking and dynamics simulations can be considered a wise, rational, and efficient way to develop therapeutic agents against COVID-19. In this way, The RNA-dependent RNA polymerase (RdRP), main protease, and spike glycoprotein of SARS-CoV-2 as well as the human angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2 are the most discussed and studied targets that play essential roles in the viral life and infection cycle. In the current in silico investigation, the guanidine functionality containing drugs and medicinal substances such as metformin, famotidine, neuraminidase inhibitors, antimalarial medications, anticancer drug imatinib, CGP compounds, and human serine protease inhibitor camostat were studied against the above-mentioned therapeutic targets and most of them (especially imatinib) have revealed an incredible spectrum of free docking scores and MD results. The current in silico investigation that its novel perspective of view is corroborated by the different experimental and clinical evaluations, confirms that the guanidine moiety can be considered as a missing promising pharmacophore in drug design and development approaches against SARS-CoV-2. Considering the chemical potency of this polyamine group in chemical interaction creation, the observed outcomes in this virtual screening were not surprising. On the other hand, the guanidine functional group has unique physico-chemical properties such as basicity that can make the target cells intracellular pH undesirable for the virus entry, uncoating, and cytosolic lifecycle. According to the obtained results in the current study that are interestingly confirmed by the previously reported efficacy of some the guanidine carrying drugs in COVID-19, guanidine as a potential multi-target anti-SARS-CoV-2 functional scaffold deserves further comprehensive investigations. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11696-022-02528-y.

show abstract

“…Interference with this region, however, may affect viral fusion with the host cell membrane preventing viral entry and infection. Indeed, recent cryoEM, X-ray crystallography and membrane fusion assays show broad inhibition of the virus through areas other than the RBD (33)(34)(35)(60)(61)(62). Thus, binding by SP-A to the S2 region responsible for conformational destabilization of both the S1 and S2 segments may prevent viral entry to the host cell (9,63).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the RBD might be protected from SP-A access by glycosylation shielding (7). Further, targeted binding to the S2 fusion region was recently shown to effectively inhibit SARS-CoV-2 function (33)(34)(35)(36), suggesting that the RBD may not be an exclusive target for viral inhibition. Importantly, SP-A preferentially targets carbohydrate moieties such as glycosylation sites that can be found in either the S1 or the S2 regions.…”

Section: Introductionmentioning

confidence: 99%

SP-A binding to the SARS-CoV-2 spike protein using hybrid quantum and classical in silico modeling and molecular pruning by Quantum Approximate Optimization Algorithm (QAOA) Based MaxCut with ZDOCK

et al. 2022

View full text Add to dashboard Cite

The pulmonary surfactant protein A (SP-A) is a constitutively expressed immune-protective collagenous lectin (collectin) in the lung. It binds to the cell membrane of immune cells and opsonizes infectious agents such as bacteria, fungi, and viruses through glycoprotein binding. SARS-CoV-2 enters airway epithelial cells by ligating the Angiotensin Converting Enzyme 2 (ACE2) receptor on the cell surface using its Spike glycoprotein (S protein). We hypothesized that SP-A binds to the SARS-CoV-2 S protein and this binding interferes with ACE2 ligation. To study this hypothesis, we used a hybrid quantum and classical in silico modeling technique that utilized protein graph pruning. This graph pruning technique determines the best binding sites between amino acid chains by utilizing the Quantum Approximate Optimization Algorithm (QAOA)-based MaxCut (QAOA-MaxCut) program on a Near Intermediate Scale Quantum (NISQ) device. In this, the angles between every neighboring three atoms were Fourier-transformed into microwave frequencies and sent to a quantum chip that identified the chemically irrelevant atoms to eliminate based on their chemical topology. We confirmed that the remaining residues contained all the potential binding sites in the molecules by the Universal Protein Resource (UniProt) database. QAOA-MaxCut was compared with GROMACS with T-REMD using AMBER, OPLS, and CHARMM force fields to determine the differences in preparing a protein structure docking, as well as with Goemans-Williamson, the best classical algorithm for MaxCut. The relative binding affinity of potential interactions between the pruned protein chain residues of SP-A and SARS-CoV-2 S proteins was assessed by the ZDOCK program. Our data indicate that SP-A could ligate the S protein with a similar affinity to the ACE2-Spike binding. Interestingly, however, the results suggest that the most tightly-bound SP-A binding site is localized to the S2 chain, in the fusion region of the SARS-CoV-2 S protein, that is responsible for cell entry Based on these findings we speculate that SP-A may not directly compete with ACE2 for the binding site on the S protein, but interferes with viral entry to the cell by hindering necessary conformational changes or the fusion process.

show abstract

Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation

Cited by 121 publications

References 56 publications

Transmembrane serine protease TMPRSS2 implicated in SARS-CoV-2 infection is autoactivated intracellularly and requires N-glycosylation for regulation

Transmembrane serine protease TMPRSS2 implicated in SARS-CoV-2 infection is autoactivated intracellularly and requires N-glycosylation for regulation

In silico investigation of the therapeutic and prophylactic potential of medicinal substances bearing guanidine moieties against COVID-19

SP-A binding to the SARS-CoV-2 spike protein using hybrid quantum and classical in silico modeling and molecular pruning by Quantum Approximate Optimization Algorithm (QAOA) Based MaxCut with ZDOCK

Contact Info

Product

Resources

About