Denovo designing, retro-combinatorial synthesis, and molecular dynamics analysis identify novel antiviral VTRM1.1 against RNA-dependent RNA polymerase of SARS CoV2 virus

Tiwari, Vishvanath

doi:10.1016/j.ijbiomac.2020.12.223

Cited by 14 publications

(11 citation statements)

References 27 publications

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“…Poustforoosh and colleagues [ 74 ] virtually screened 28 compounds against two active sites of RdRp by rigid and induced-fit docking, and found that tenofovir had lower docking scores than other tested drugs. Similar findings were obtained by Tiwari [ 75 ]. In a further study by Elficky [ 76 ], the researcher applied a molecular dynamics simulation (MDS) approach to test the binding affinity of several compounds to different dynamic states of the RdRp protein.…”

Section: Pre-clinical Studiessupporting

confidence: 91%

“…As reviewed in this work, several in silico studies suggest the inhibitory activity of tenofovir and its derivative prodrugs TDF and TAF on their presumed and more obvious viral target, the SARS-CoV-2 RdRp protein, likely competing with the natural nucleotide adenosine for the enzyme binding and then acting as chain terminators [ 50 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. Notably, in one of these studies [ 81 ] a better binding activity of tenofovir with the P323L mutated RdRp protein was observed in comparison with remdesivir, further suggesting tenofovir use in COVID-19 treatment.…”

Section: Discussionmentioning

confidence: 99%

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Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

et al. 2021

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide with different clinical manifestations. Age and comorbidities may explain severity in critical cases and people living with human immunodeficiency virus (HIV) might be at particularly high risk for severe progression. Nonetheless, current data, although sometimes contradictory, do not confirm higher morbidity, risk of more severe COVID-19 or higher mortality in HIV-infected people with complete access to antiretroviral therapy (ART). A possible protective role of ART has been hypothesized to explain these observations. Anti-viral drugs used to treat HIV infection have been repurposed for COVID-19 treatment; this is also based on previous studies on severe acute respiratory syndrome virus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV). Among them, lopinavir/ritonavir, an inhibitor of viral protease, was extensively used early in the pandemic but it was soon abandoned due to lack of effectiveness in clinical trials. However, remdesivir, a nucleotide analog that acts as reverse-transcriptase inhibitor, which was tested early during the pandemic because of its wide range of antiviral activity against several RNA viruses and its safety profile, is currently the only antiviral medication approved for COVID-19. Tenofovir, another nucleotide analog used extensively for HIV treatment and pre-exposure prophylaxis (PrEP), has also been hypothesized as effective in COVID-19. No data on tenofovir’s efficacy in coronavirus infections other than COVID-19 are currently available, although information relating to SARS-CoV-2 infection is starting to come out. Here, we review the currently available evidence on tenofovir’s efficacy against SARS-CoV-2.

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Section: Pre-clinical Studiessupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

et al. 2021

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“…Considering these data and the existence of a drug already licensed containing an association of TDF with FTC, we decided to carry out the present clinical study controlled with a placebo, including groups treated with TDF alone and with TDF combined with FTC. Several reports of preclinical studies of these drugs for SARS-CoV-2 have been found, including several in silico studies, which have shown the ability of TDF to bind to RdRp of SARS-CoV-2 7,[38][39][40][41][42][43][44][45][46] . TDF also binds with other important virus proteins, including the papain-like protease (PLpro) and the main or 3C-like protease (Mpro/3CLpro) [47][48][49] , in addition to interacting with the S protein and the ACE2 receptor 50,51 , suggesting multiple binding and interference targets in the replication cycle of the virus.…”

Section: Efficacy and Toxicity Of Tdf And Tdf Combined With Ftc In Covid-19mentioning

confidence: 99%

Clinical Trial of Efficacy and Toxicity of Disoproxil Tenofovir Fumarate and Emtricitabine for Mild to Moderate SARS-CoV-2 Infections

Arruda¹,

Pires-Neto²,

Medeiros³

et al. 2021

Preprint

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This study aimed to evaluate the efficacy and toxicity of tenofovir (TDF) and TDF combined with emtricitabine (TDF/FTC) in patients with mild to moderate COVID-19 infections. We conducted a randomized, double-blind, placebo-controlled clinical trial in patients with clinical suspicion of mild to moderate respiratory infection caused by SARS-CoV-2 who were treated at an outpatient clinic. Patients were randomly recruited to take 10 days of TDF (300 mg/day), TDF (300 mg/day) combined with FTC (200 mg/day) or placebo Vitamin C (500 mg/day). The primary parameter was the score of symptoms and predictive signs of COVID-19, assessed on the seventh day of patient follow-up. From a total of 309 patients with clinical suspicion of SARS-CoV-2, 227 met the inclusion criteria and were randomly distributed into the following groups: (a) 75 (one did not initiate treatment) in the TDF group; (b) 74 in the TDF combined with FTC group; and (c) 77 in the Vitamin C group (placebo). Of the 226 patients, 139 (62%) were positive for SARS-CoV-2. Fever (37.8oC), ageusia or dysgeusia, anosmia or dysosmia, and two or more clinical symptoms or signs were significantly associated with SARS-CoV-2 infection. There was no significant change in clinical score based on clinical symptoms and signs between treatment groups. Patients with mild to moderate infection by SARS-CoV-2 had higher concentrations of G-CSF, IL-1β, IL-6 and TNF-α compared to patients without infection. Patients with mild to moderate respiratory infection, with fever (37.8oC), loss of smell, loss of taste and two or more symptoms, have a better prediction for the diagnosis of COVID-19. Patients with SARS-CoV-2 showed higher and more persistent proinflammatory cytokines profile compared to patients not infected with SARS-CoV-2. Pharmacological intervention with TDF or TDF combined with FTC did not change the clinical signs and symptoms score in mild to moderate respiratory infection in patients with SARS-CoV-2 compared to the Vitamin C group (placebo).

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“…The Molecular Dynamics Simulation (MDS) analysis was performed by Desmond using the OPLS3e force field and TIP3P solvent. MDS was run for 50ns in duplicate as per published methods (Tiwari, 2021). In brief, the system was built by selecting TIP3P water as a solvent; the system's charge was neutralized by adding twenty-nine sodium ions, the system was made close to the natural system by adding 0.15M NaCl.…”

Section: Molecular Dynamics Simulationmentioning

confidence: 99%

Immunoinformatic approach to design a multiepitope vaccine targeting non-mutational hotspot regions of structural and non-structural proteins of the SARS CoV2

Solanki¹,

Tiwari²,

Tiwari³

2021

PeerJ

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Background The rapid Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV2) outbreak caused severe pandemic infection worldwide. The high mortality and morbidity rate of SARS CoV2 is due to the unavailability of vaccination and mutation in this virus. The present article aims to design a potential vaccine construct VTC3 targeting the non-mutational region of structural and non-structural proteins of SARS CoV2. Methods In this study, vaccines were designed using subtractive proteomics and reverse vaccinology. To target the virus adhesion and evasion, 10 different structural and non-structural proteins have been selected. Shortlisted proteins have been screened for B cell, T cell and IFN gamma interacting epitopes. 3D structure of vaccine construct was modeled and evaluated for its physicochemical properties, immunogenicity, allergenicity, toxicity and antigenicity. The finalized construct was implemented for docking and molecular dynamics simulation (MDS) with different toll-like receptors (TLRs) and human leukocyte antigen (HLA). The binding energy and dissociation construct of the vaccine with HLA and TLR was also calculated. Mutational sensitivity profiling of the designed vaccine was performed, and mutations were reconfirmed from the experimental database. Antibody production, clonal selection, antigen processing, immune response and memory generation in host cells after injection of the vaccine was also monitored using immune simulation. Results Subtractive proteomics identified seven (structural and non-structural) proteins of this virus that have a role in cell adhesion and infection. The different epitopes were predicted, and only extracellular epitopes were selected that do not have similarity and cross-reactivity with the host cell. Finalized epitopes of all proteins with minimum allergenicity and toxicity were joined using linkers to designed different vaccine constructs. Docking different constructs with different TLRs and HLA demonstrated a stable and reliable binding affinity of VTC3 with the TLRs and HLAs. MDS analysis further confirms the interaction of VTC3 with HLA and TLR1/2 complex. The VTC3 has a favorable binding affinity and dissociation constant with HLA and TLR. The VTC3 does not have similarities with the human microbiome, and most of the interacting residues of VTC3 do not have mutations. The immune simulation result showed that VTC3 induces a strong immune response. The present study designs a multiepitope vaccine targeting the non-mutational region of structural and non-structural proteins of the SARS CoV2 using an immunoinformatic approach, which needs to be experimentally validated.

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Denovo designing, retro-combinatorial synthesis, and molecular dynamics analysis identify novel antiviral VTRM1.1 against RNA-dependent RNA polymerase of SARS CoV2 virus

Cited by 14 publications

References 27 publications

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

Clinical Trial of Efficacy and Toxicity of Disoproxil Tenofovir Fumarate and Emtricitabine for Mild to Moderate SARS-CoV-2 Infections

Immunoinformatic approach to design a multiepitope vaccine targeting non-mutational hotspot regions of structural and non-structural proteins of the SARS CoV2

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