The current state of validated small molecules inhibiting SARS-CoV-2 nonstructural proteins.
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ABSTRACT:
SUBMITTER: Kocabas F
PROVIDER: S-EPMC8573838 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated coronavirus disease 2019 (COVID-19) infection remains a global pandemic and health emergency with overwhelming social and economic impacts throughout the world. Therapeutics for COVID-19 are limited to only remdesivir; therefore, there is a need for combined, multidisciplinary efforts to develop new therapeutic molecules and explore the effectiveness of existing drugs against SARS-CoV-2. In the present study, we reported eight (SCOV-L-02, SCOV-L-09, SCOV-L-10, SCOV-L-11, SCOV-L-15, SCOV-L-18, SCOV-L-22, and SCOV-L-23) novel structurally related small-molecule derivatives of niclosamide (SCOV-L series) for their targeting potential against angiotensin-converting enzyme-2 (ACE2), type II transmembrane serine protease (TMPRSS2), and SARS-COV-2 nonstructural proteins (NSPs) including NSP5 (3CLpro), NSP3 (PLpro), and RdRp. Our correlation analysis suggested that ACE2 and TMPRSS2 modulate host immune response via regulation of immune-infiltrating cells at the site of tissue/organs entries. In addition, we identified some TMPRSS2 and ACE2 microRNAs target regulatory networks in SARS-CoV-2 infection and thus open up a new window for microRNAs-based therapy for the treatment of SARS-CoV-2 infection. Our in vitro study revealed that with the exception of SCOV-L-11 and SCOV-L-23 which were non-active, the SCOV-L series exhibited strict antiproliferative activities and non-cytotoxic effects against ACE2- and TMPRSS2-expressing cells. Our molecular docking for the analysis of receptor-ligand interactions revealed that SCOV-L series demonstrated high ligand binding efficacies (at higher levels than clinical drugs) against the ACE2, TMPRSS2, and SARS-COV-2 NSPs. SCOV-L-18, SCOV-L-15, and SCOV-L-09 were particularly found to exhibit strong binding affinities with three key SARS-CoV-2's proteins: 3CLpro, PLpro, and RdRp. These compounds bind to the several catalytic residues of the proteins, and satisfied the criteria of drug-like candidates, having good adsorption, distribution, metabolism, excretion, and toxicity (ADMET) pharmacokinetic profile. Altogether, the present study suggests the therapeutic potential of SCOV-L series for preventing and managing SARs-COV-2 infection and are currently under detailed investigation in our lab.
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Project description:SARS-CoV-2 (COVID-19) epidemic has created an unprecedented medical and economic crisis all over the world. SARS-CoV-2 is found to have more contagious character as compared to MERS-CoV and is spreading in a very fast manner all around the globe. It has affected over 31 million people all over the world till date. This virus shares around 80% of genome similarity with SARS-CoV. In this perspective, we have explored three major targets namely; SARS-CoV-2 spike (S) protein, RNA dependent RNA polymerase, and 3CL or Mpro Protease for the inhibition of SARS-CoV-2. These targets have attracted attention of the medicinal chemists working on computer-aided drug design in developing new small molecules that might inhibit these targets for combating COVID-19 disease. Moreover, we have compared the similarity of these target proteins with earlier reported coronavirus (SARS-CoV). We have observed that both the coronaviruses share around 80% similarity in their amino acid sequence. The key amino acid interactions which can play a crucial role in designing new small molecule inhibitors against COVID-19 have been reported in this perspective. Authors believe that this study will help the medicinal chemists to understand the key amino acids essential for interactions at the active site of target proteins in SARS-CoV-2, based on their similarity with earlier reported viruses. In this review, we have also described the lead molecules under various clinical trials for their efficacy against COVID-19.
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Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) pandemic. Several variants of SARS-CoV-2 have emerged worldwide. These variants show different transmissibility infectivity due to mutations in the viral spike (S) glycoprotein that interacts with the human angiotensin-converting enzyme 2 (hACE2) receptor and facilitates viral entry into target cells. Despite the effective SARS-CoV-2 vaccines, we still need to identify selective antivirals, and the S glycoprotein is a key target to neutralize the virus. We hypothesize that small molecules could disrupt the interaction of S glycoprotein with hACE2 and inhibit viral entry. We analyzed the S glycoprotein-hACE2 complex structure (PDB: 7DF4) and created models for different viral variants using visual molecular dynamics (VMD) and molecular operating environment (MOE) programs. Moreover, we started the hits search by performing structure-based molecular docking virtual screening of commercially available small molecules against S glycoprotein models using OEDocking FRED-4.0.0.0 software. The FRED-4.0.0.0 Chemguass4 scoring function was used to rank the small molecules based on their affinities. The best candidate compounds were purchased and tested using a standard SARS-CoV-2 pseudotyped cell-based bioassay to investigate their antiviral activity. Three of these compounds, alone or in combination, showed antiviral selectivity. These small molecules may lead to an effective antiviral treatment or serve as probes to better understand the biology of SARS-CoV-2.
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Project description:The disease caused by viral pneumonia called severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) declared by the World Health Organization is a global pandemic that the world has witnessed since the last Ebola epidemic, SARS and MERS viruses. Many chemical compounds with antiviral activity are currently undergoing clinical investigation in order to find treatments for SARS-CoV-2 infected patients. On-going drug-drug interaction examinations on new, existing, and repurposed antiviral drugs are yet to provide adequate safety, toxicological, and effective monitoring protocols. This review presents an overview of direct and indirect antiviral drugs, antibiotics, and immune-stimulants used in the management of SARS-CoV-2. It also seeks to outline the recent development of drugs with anti-coronavirus effects; their mono and combination therapy in managing the disease vis-à-vis their biological sources and chemistry. Co-administration of these drugs and their interactions were discussed to provide significant insight into how adequate monitoring of patients towards effective health management could be achieved.
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Project description:Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a virus belonging to the Coronavirus family, is now known to cause Coronavirus Disease (Covid-19) which was first recognized in December 2019. Covid-19 leads to respiratory illnesses ranging from mild infections to pneumonia and lung failure. Strikingly, within a few months of its first report, Covid-19 has spread worldwide at an exceptionally high speed and it has caused enormous human casualties. As yet, there is no specific treatment for Covid-19. Designing inhibitory drugs that can interfere with the viral entry process constitutes one of the main preventative therapies that could combat SARS-CoV-2 infection at an early stage. In this review, we provide a brief introduction of the main features of coronaviruses, discuss the entering mechanism of SARS-CoV-2 into human host cells and review small molecules that inhibit SARS-CoV-2 entry into host cells. Specifically, we focus on small molecules, identified by experimental validation and/or computational prediction, that target the SARS-CoV-2 spike protein, human angiotensin converting enzyme 2 (ACE2) receptor and the different host cell proteases that activate viral fusion. Given the persistent rise in Covid-19 cases to date, efforts should be directed towards validating the therapeutic effectiveness of these identified small molecule inhibitors.
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