Design of novel disturbing peptides against ACE2 SARS-CoV-2 spike-binding region by computational approaches

The SARS-CoV-2, the virus which is responsible for COVID-19 disease, employs its spike protein to recognize its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequently enters the host cell. In this process, the receptor-binding domain (RBD) of the spike has an interface with the α1-helix of the peptidase domain (PD) of ACE2. This study focuses on the disruption of the protein-protein interaction (PPI) of RBD-ACE2. Among the residues in the template (which was extracted from the ACE2), those with unfavorable energies were selected for substitution by mutagenesis. As a result, a library of 140 peptide candidates was constructed and the binding affinity of each candidate was evaluated by molecular docking and molecular dynamics simulations against the α1-helix of ACE2. Finally, the most potent peptides P23 (GFNNYFPHQSYGFMPTNGVGY), P28 (GFNQYFPHQSYGFPPTNGVGY), and P31 (GFNRYFPHQSYGFCPTNGVGY) were selected and their dynamic behaviors were studied. The results showed peptide inhibitors increased the radius, surface accessible area, and overall mobility of residues of the protein. However, no significant alteration was seen in the key residues in the active site. Meanwhile, they can be proposed as promising agents against COVID-19 by suppressing the viral attachment and curbing the infection at its early stage. The designed peptides showed potency against beta, gamma, delta, and omicron variants of SARS-CoV-2.

Rapid review and meta-analysis of adverse events associated with molnupiravir in patients with COVID-19.

AIMS: The aim of this study was to evaluate the safety profile of molnupiravir in COVID-19 patients. METHODS: PubMed, Cochrane Library, medRxive and Google Scholar were searched for articles published up to April 25, 2022. Meta-analysis was performed using Comprehensive Meta-Analysis software. RESULTS: Four trials involving 2241 patients met the inclusion criteria. No significant difference was observed between molnupiravir at 200, 400 and 800 mg compared with placebo (200 mg: risk ratio [RR] = 0.97; 95% confidence interval [CI]: 0.78-1.20; P = .80; 400 mg: RR = 0.81; 95% CI: 0.64-1.02; P = .07; 800 mg: RR = 0.94; 95% CI: 0.83-1.06; P = .36) for any adverse events (AEs); at 200, 400 and 800 mg compared with placebo (200 mg: RR = 0.81; 95% CI: 0.41-1.63; P = .57; 400 mg: RR = 0.82; 95% CI: 0.41-1.61; P = .56; 800 mg: RR = 0.80; 95% CI: 0.59-1.08; P = .15) for serious adverse events; at 200, 400 and 800 mg compared with placebo (200 mg: RR = 1.74; 95% CI: 0.48-6.30; P = .39; 400 mg: RR = 1.07; 95% CI: 0.28-4.09; P = .91; 800 mg: RR = 0.47; 95% CI: 0.17-1.28; P = .14) for AEs leading to death; and at 200, 400 and 800 mg compared with placebo (200 mg: RR = 1.50; 95% CI: 0.26-8.55; P = .64; 400 mg: RR = 0.99; 95% CI: 0.17-5.68; P = .99; 800 mg: RR = 0.61; 95% CI: 0.31-1.23; P = .17) for treatment discontinuation due to AEs. CONCLUSION: This meta-analysis showed that the use of three doses of molnupiravir (200, 400 and 800 mg) is safe for COVID-19 patients. Further research is needed to confirm the present findings.

Artesunate, imatinib, and infliximab in COVID‐19: A rapid review and meta‐analysis of current evidence

Background and Objective Despite the pervasive vaccination program against coronavirus disease 2019 (COVID‐19), people who got fully vaccinated are still contaminated by severe acute respiratory syndrome coronavirus 2, making an effective and safe therapeutic intervention a crucial need for the patients' survival. The purpose of the present study is to seek available evidence for the efficacy and safety of three promising medications artesunate, imatinib, and infliximab against COVID‐19. Methods A literature search was conducted in PubMed, Cochrane Library, medRxive, and Google Scholar, and the relevant articles published up to January 2022 were found. Furthermore, the clinical trial databases were screened for finding more citations. Data analysis was carried out applying The Cochrane Collaboration tool and Newcastle–Ottawa scale to assess the included studies. Meta‐analysis was performed using RevMan 5.4.1. Results Five published studies were identified as eligible. Meta‐analysis showed that there was no significant difference between the infliximab and control groups in terms of mortality rate (risk ratio [RR]: 0.65;confidence interval [CI] 95%: 0.40–1.07;p = .09). However, a significant difference was observed between the two groups for the hospital discharge (RR: 1.37;CI 95%: 1.04–1.80;p = .03). No remarkable clinical benefit was observed for using imatinib in COVID‐19 patients. Artesunate showed significant improvement in patients with COVID‐19. Conclusion In the present, limited evidence exists for the efficacy and safety of artesunate, imatinib, and infliximab in patients with COVID‐19. The findings of WHO's Solidarity international trial will provide further information regarding these therapeutic interventions. Our purpose was to review the available evidence of these three drugs in the treatment of coronavirus disease 2019 (COVID‐19). Our findings showed little evidence for the efficacy and safety of artesunate, imatinib, and infliximab in patients with COVID‐19.

Inhibition of SARS-CoV-2 pathogenesis by potent peptides designed by the mutation of ACE2 binding region.

The outbreak of COVID-19 has resulted in millions of deaths. Despite all attempts that have been made to combat the pandemic, the re-emergence of new variants complicated SARS-CoV-2 eradication. The ongoing global spread of COVID-19 demands the incessant development of novel agents in vaccination, diagnosis, and therapeutics. Targeting receptor-binding domain (RBD) of spike protein by which the virus identifies host receptor, angiotensin-converting enzyme (ACE2), is a promising strategy for curbing viral infection. This study aims to discover novel peptide inhibitors against SARS-CoV-2 entry using computational approaches. The RBD binding domain of ACE2 was extracted and docked against the RBD. MMPBSA calculations revealed the binding energies of each residue in the template. The residues with unfavorable binding energies were considered as mutation spots by OSPREY. Binding energies of the residues in RBD-ACE2 interface was determined by molecular docking. Peptide inhibitors were designed by the mutation of RBD residues in the virus-receptors complex which had unfavorable energies. Peptide tendency for RBD binding, safety, and allergenicity were the criteria based on which the final hits were screened among the initial library. Molecular dynamics simulations also provided information on the mechanisms of inhibitory action in peptides. The results were finally validated by molecular docking simulations to make sure the peptides are capable of hindering virus-host interaction. Our results introduce three peptides P7 (RAWTFLDKFNHEAEDLRYQSSLASWN), P13 (RASTFLDKFNHEAEDLRYQSSLASWN), and P19 (RADTFLDKFNHEAEDLRYQSSLASWN) as potential effective inhibitors of SARS-CoV-2 entry which could be considered in drug development for COVID-19 treatment.

Artesunate, imatinib, and infliximab in COVID-19: A rapid review and meta-analysis of current evidence.

BACKGROUND AND OBJECTIVE: Despite the pervasive vaccination program against coronavirus disease 2019 (COVID-19), fully vaccinated people are still being infected by severe acute respiratory syndrome coronavirus 2, making an effective and safe therapeutic intervention a crucial need for the patients' survival. The purpose of the present study is to seek available evidence for the efficacy and safety of three promising medications artesunate, imatinib, and infliximab against COVID-19. METHODS: A literature search was conducted in PubMed, Cochrane Library, medRxive, and Google Scholar up to January 2022. Furthermore, the clinical trial databases were screened to find more citations. The Cochrane Collaboration tool and Newcastle-Ottawa scale were used to assess the included studies. Meta-analysis was performed using RevMan 5.4.1. RESULTS: Five published studies were identified as eligible. Meta-analysis showed that there was no significant difference between the infliximab and control groups in terms of mortality rate (risk ratio [RR]: 0.65; 95% confidence interval [CI]: 0.40-1.07; p = 0.09). However, a significant difference was observed between the two groups for the hospital discharge (RR: 1.37; 95% CI: 1.04-1.80; p = 0.03). No remarkable clinical benefit was observed in favor of using imatinib for COVID-19 patients. Artesunate showed significant improvement in patients with COVID-19. CONCLUSION: In the present, limited evidence exists for the efficacy and safety of artesunate, imatinib, and infliximab in patients with COVID-19. The findings of WHO's Solidarity international trial will provide further information regarding these therapeutic interventions.

Efficacy and safety of arbidol (umifenovir) in patients with COVID-19: A systematic review and meta-analysis.

OBJECTIVE: To provide the latest evidence for the efficacy and safety of arbidol (umifenovir) in COVID-19 treatment. METHODS: A literature systematic search was carried out in PubMed, Cochrane Library, Embase, and medRxiv up to May 2021. The Cochrane risk of bias tool and Newcastle-Ottawa scale were used to assess the quality of included studies. Meta-analysis was performed using RevMan 5.3. RESULTS: Sixteen studies were met the inclusion criteria. No significant difference was observed between arbidol and non-antiviral treatment groups neither for primary outcomes, including the negative rate of PCR (NR-PCR) on Day 7 (risk ratio [RR]: 0.94; 95% confidence interval (CI): 0.78-1.14) and Day 14 (RR: 1.10; 95% CI: 0.96-1.25), and PCR negative conversion time (PCR-NCT; mean difference [MD]: 0.74; 95% CI: -0.87 to 2.34), nor secondary outcomes (p > .05). However, arbidol was associated with higher adverse events (RR: 2.24; 95% CI: 1.06-4.73). Compared with lopinavir/ritonavir, arbidol showed better efficacy for primary outcomes (p < .05). Adding arbidol to lopinavir/ritonavir also led to better efficacy in terms of NR-PCR on Day 7 and PCR-NCT (p < .05). There was no significant difference between arbidol and chloroquine in primary outcomes (p > .05). No remarkable therapeutic effect was observed between arbidol and other agents (p > .05). CONCLUSION: The present meta-analysis showed no significant benefit of using arbidol compared with non-antiviral treatment or other therapeutic agents against COVID-19 disease. High-quality studies are needed to establish the efficacy and safety of arbidol for COVID-19.