Antiviral Molecules Research Articles

Current status of silica-based nanoparticles as therapeutics and its potential as therapies against viruses

In the past decade, interest in nanoparticles for clinical indications has been steadily gaining traction. Most recently, Lipid Nanoparticles (LNP) have been used successfully to construct the SARS-CoV-2 mRNA vaccines for rapid pandemic response. Similarly, silica is another nanomaterial which holds much potential to create nanomedicines against pathogens of interest. One major advantage of silica-based nanoparticles is its crystalline and highly ordered structure, which can be specifically tuned to achieve the desired properties needed for clinical applications. Increasingly, clinical research has shown the potential of silica nanoparticles not only as an antiviral, but also its ability as a delivery system for antiviral small molecules and vaccines against viruses. Silica has an excellent biosafety profile and has been tested in several early phase clinical trials since 2012, demonstrating good tolerability and minimal reported side effects. In this review, we discuss the clinical development of silica nanoparticles to date and identify the gaps and potential pitfalls in its path to clinical translation.

Interferon-induced restriction of Chikungunya virus infection

Chikungunya virus (CHIKV) is an enveloped RNA virus that causes Chikungunya fever (CHIKF), which is transmitted to humans through the bite of infected Aedes mosquitos. Although CHIKVF had been regarded as an endemic disease in limited regions of Africa and Asia, the recent global reemergence of CHIKV heightened awareness of this infectious disease, and CHIKV infection is currently considered an increasing threat to public health. However, no specific drug or licensed vaccine is available for CHIKV infection. As seen in other RNA virus infections, CHIKV triggers the interferon (IFN) response that plays a central role in host defense against pathogens. Experimental evidence has demonstrated that control of CHIVK replication by the IFN response is achieved by antiviral effector molecules called interferon-stimulated genes (ISGs), whose expressions are upregulated by IFN stimulation. This review details the molecular basis of the IFN-mediated suppression of CHIKV, particularly the ISGs restricting CHIKV replication.

A pan-serotype antiviral to prevent and treat dengue: A journey from discovery to clinical development driven by public-private partnerships

While progress has been made in fighting diseases disproportionally affecting underserved populations, unmet medical needs persist for many neglected tropical diseases. The World Health Organization has encouraged strong public-private partnerships to address this issue and several public and private organizations have set an example in the past showing a strong commitment to combat these diseases. Pharmaceutical companies are contributing in different ways to address the imbalance in research efforts. With this review, we exemplify the role of a public-private partnership in research and development by the journey of our dengue antiviral molecule that is now in early clinical development. We detail the different steps of drug development and outline the contribution of each partner to this process. Years of intensive collaboration resulted in the identification of two antiviral compounds, JNJ-A07 and JNJ-1802, the latter of which has advanced to clinical development.

Full-Length Transcriptome of Myotis pilosus as a Reference Resource and Mining of Auditory and Immune Related Genes.

Rickett's big-footed bat, Myotis pilosus, which belongs to the family Vespertilionida, is the only known piscivorous bat in East Asia. Accurate whole genome and transcriptome annotations are essential for the study of bat biological evolution. The lack of a whole genome for M. pilosus has limited our understanding of the molecular mechanisms underlying the species' evolution, echolocation, and immune response. In the present work, we sequenced the entire transcriptome using error-corrected PacBio single-molecule real-time (SMRT) data. Then, a total of 40 GB of subreads were generated, including 29,991 full-length non-chimeric (FLNC) sequences. After correction by Illumina short reads and de-redundancy, we obtained 26,717 error-corrected isoforms with an average length of 3018.91 bp and an N50 length of 3447 bp. A total of 1528 alternative splicing (AS) events were detected by transcriptome structural analysis. Furthermore, 1032 putative transcription factors (TFs) were identified, with additional identification of several long non-coding RNAs (lncRNAs) with high confidence. Moreover, several key genes, including PRL-2, DPP4, Glul, and ND1 were also identified as being associated with metabolism, immunity, nervous system processes, and auditory perception. A multitude of pattern recognition receptors was identified, including NLR, RLR, SRCR, the antiviral molecule IRF3, and the IFN receptor subunit IFNAR1. High-quality reference genomes at the transcriptome level may be used to quantify gene or transcript expression, evaluate alternative splicing levels, identify novel transcripts, and enhance genome annotation in bats.

Dual roles and potential applications of exosomes in HCV infections.

The hepatitis C virus (HCV) causes severe liver diseases, including hepatitis, liver cirrhosis, and hepatocellular carcinoma, which have high morbidity and mortality. Antibody targeting receptor-mediated HCV infections have limited therapeutic benefits, suggesting that the transmission of HCV infections is possibly mediated via receptor-independent mechanisms. Exosomes are membrane-enclosed vesicles with a diameter of 30-200 nm, which originate from the fusion of endosomal multivesicular bodies with the plasma membrane. Accumulating evidence suggests that exosomes have a pivotal role in HCV infections. Exosomes can transfer viral and cellular bioactive substances, including nucleic acids and proteins, to uninfected cells, thus spreading the infection by masking these materials from immunological recognition. In addition, exosomes originating from some cells can deliver antiviral molecules or prompt the immune response to inhibit HCV infection. Exosomes can be used for the diagnosis of HCV-related diseases, and are being presently evaluated as therapeutic tools for anti-HCV drug delivery. This review summarizes the current knowledge on the dual roles and potential clinical applications of exosomes in HCV infections.

Engineering antiviral immune-like systems for autonomous virus detection and inhibition in mice

The ongoing COVID-19 pandemic has demonstrated that viral diseases represent an enormous public health and economic threat to mankind and that individuals with compromised immune systems are at greater risk of complications and death from viral diseases. The development of broad-spectrum antivirals is an important part of pandemic preparedness. Here, we have engineer a series of designer cells which we term autonomous, intelligent, virus-inducible immune-like (ALICE) cells as sense-and-destroy antiviral system. After developing a destabilized STING-based sensor to detect viruses from seven different genera, we have used a synthetic signal transduction system to link viral detection to the expression of multiple antiviral effector molecules, including antiviral cytokines, a CRISPR-Cas9 module for viral degradation and the secretion of a neutralizing antibody. We perform a proof-of-concept study using multiple iterations of our ALICE system in vitro, followed by in vivo functionality testing in mice. We show that dual output ALICESaCas9+Ab system delivered by an AAV-vector inhibited viral infection in herpetic simplex keratitis (HSK) mouse model. Our work demonstrates that viral detection and antiviral countermeasures can be paired for intelligent sense-and-destroy applications as a flexible and innovative method against virus infection.

A Broad-Spectrum Antiviral Molecule, Protoporphyrin IX, Acts as a Moderator of HIV-1 Capsid Assembly by Targeting the Capsid Hexamer.

The capsid protein (CA), an essential component of human immunodeficiency virus type 1 (HIV-1), represents an appealing target for antivirals. Small molecules targeting the CAI-binding cavity in the C-terminal domain of HIV-1 CA (CA CTD) confer potent antiviral activities. In this study, we report that a small molecule, protoporphyrin IX (PPIX), targets the HIV-1 CA by binding to this pocket. PPIX was identified via in vitro drug screening, using a homogeneous and time-resolved fluorescence-based assay. CA multimerization and a biolayer interferometry (BLI) assay showed that PPIX promoted CA multimerization and bound directly to CA. The binding model of PPIX to CA CTD revealed that PPIX forms hydrogen bonds with the L211and E212 residues in the CA CTD. Moreover, the BLI assay demonstrated that this compound preferentially binds to the CA hexamer versus the monomer. The superposition of the CAI CTD-PPIX complex and the hexameric CA structure suggests that PPIX binds to the interface formed by the NTD and the CTD between adjacent protomers in the CA hexamer via the T72 and E212 residues, serving as a glue to enhance the multimerization of CA. Taken together, our studies demonstrate that PPIX, a hexamer-targeted CA assembly enhancer, should be a new chemical probe for the discovery of modulators of the HIV-1 capsid assembly. IMPORTANCE CA and its assembled viral core play essential roles in distinct steps during HIV-1 replication, including reverse transcription, integration, nuclear entry, virus assembly, and maturation through CA-CA or CA-host factor interactions. These functions of CA are fundamental for HIV-1 pathogenesis, making it an appealing target for antiviral therapy. In the present study, we identified protoporphyrin IX (PPIX) as a candidate CA modulator that can promote CA assembly and prefers binding the CA hexamer versus the monomer. PPIX, like a glue, bound at the interfaces between CA subunits to accelerate CA multimerization. Therefore, PPIX could be used as a new lead for a CA modulator, and it holds potential research applications.

ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.

Interferon-stimulated gene 15 (ISG15) is a 15-kDa ubiquitin-like modifier that binds to target proteins in a process termed ISGylation. ISG15, first described as an antiviral molecule against many viruses, participates in numerous cellular processes, from immune modulation to the regulation of genome stability. Interestingly, the role of ISG15 as a regulator of cell metabolism has recently gained strength. We previously described ISG15 as a regulator of mitochondrial functions in bone marrow-derived macrophages (BMDMs) in the context of Vaccinia virus (VACV) infection. Here, we demonstrate that ISG15 regulates lipid metabolism in BMDMs and that ISG15 is necessary to modulate the impact of VACV infection on lipid metabolism. We show that Isg15-/- BMDMs demonstrate alterations in the levels of several key proteins of lipid metabolism that result in differences in the lipid profile compared with Isg15+/+ (wild-type [WT]) BMDMs. Specifically, Isg15-/- BMDMs present reduced levels of neutral lipids, reflected by decreased lipid droplet number. These alterations are linked to increased levels of lipases and are independent of enhanced fatty acid oxidation (FAO). Moreover, we demonstrate that VACV causes a dysregulation in the proteomes of BMDMs and alterations in the lipid content of these cells, which appear exacerbated in Isg15-/- BMDMs. Such metabolic changes are likely caused by increased expression of the metabolic regulators peroxisome proliferator-activated receptor-γ (PPARγ) and PPARγ coactivator-1α (PGC-1α). In summary, our results highlight that ISG15 controls BMDM lipid metabolism during viral infections, suggesting that ISG15 is an important host factor to restrain VACV impact on cell metabolism. IMPORTANCE The functions of ISG15 are continuously expanding, and growing evidence supports its role as a relevant modulator of cell metabolism. In this work, we highlight how the absence of ISG15 impacts macrophage lipid metabolism in the context of viral infections and how poxviruses modulate metabolism to ensure successful replication. Our results open the door to new advances in the comprehension of macrophage immunometabolism and the interaction between VACV and the host.

Validation of Promoters and Codon Optimization on CRISPR/Cas9-Engineered Jurkat Cells Stably Expressing αRep4E3 for Interfering with HIV-1 Replication

Persistent and efficient therapeutic protein expression in the specific target cell is a significant concern in gene therapy. The controllable integration site, suitable promoter, and proper codon usage influence the effectiveness of the therapeutic outcome. Previously, we developed a non-immunoglobulin scaffold, alpha repeat protein (αRep4E3), as an HIV-1 RNA packaging interference system in SupT1 cells using the lentiviral gene transfer. Although the success of anti-HIV-1 activity was evidenced, the integration site is uncontrollable and may not be practical for clinical translation. In this study, we use the CRISPR/Cas9 gene editing technology to precisely knock-in αRep4E3 genes into the adeno-associated virus integration site 1 (AAVS1) safe harbor locus of the target cells. We compare the αRep4E3 expression under the regulation of three different promoters, including cytomegalovirus (CMV), human elongation factor-1 alpha (EF1α), and ubiquitin C (UbC) promoters with and without codon optimization in HEK293T cells. The results demonstrated that the EF1α promoter with codon-optimized αRep4E3mCherry showed higher protein expression than other promoters with non-optimized codons. We then performed a proof-of-concept study by knocking in the αRep4E3mCherry gene at the AAVS1 locus of the Jurkat cells. The results showed that the αRep4E3mCherry-expressing Jurkat cells exhibited anti-HIV-1 activities against HIV-1NL4-3 strain as evidenced by decreased capsid (p24) protein levels and viral genome copies as compared to the untransfected Jurkat control cells. Altogether, our study demonstrates that the αRep4E3 could interfere with the viral RNA packaging and suggests that the αRep4E3 scaffold protein could be a promising anti-viral molecule that offers a functional cure for people living with HIV-1.

Emerging Arboviruses of Public Health Concern in Africa: Priorities for Future Research and Control Strategies

Arboviruses are most prevalent in tropical and subtropical regions, where arthropods are widespread. The World Health Organization (WHO) estimated that the mortality burden of arbovirus diseases, such as yellow fever in Africa, was 84,000–170,000 severe cases and 29,000–60,000 deaths in 2013. These epidemics emphasize the urgent need for integrated control and prevention of arboviral diseases. Challenges in managing and controlling arboviral diseases in Africa are mainly attributed to poor insect vector control, insecticide resistance, and poor sanitation and solid waste management. The removal or reduction of mosquito populations amongst susceptible individuals is identified as the most effective measure to control many vector-borne diseases. Current public health needs call for efficient vector control programs and maintenance of adequate surveillance systems through the availability of trained personnel and rapid diagnostic facilities, providing an interdisciplinary response to control and mitigate the threats of emerging and re-emerging arboviruses. Furthermore, research priorities should focus on understanding the factors responsible for adaptation to other vectors, determinants of infection and transmission, and the development of high efficiency antiviral molecules or candidate vaccines. Here, we explore and review our current understanding of arboviruses of public health importance in Africa, with a focus on emerging arboviruses, their arthropod vectors, and the epidemiology of major arboviruses. Finally, we appraise the role of planetary health in addressing the threat of arboviruses and identify other priority areas of research for effective control.

Repositioning of anti-dengue compounds against SARS-CoV-2 as viral polyprotein processing inhibitor.

A therapy for COVID-19 (Coronavirus Disease 19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) remains elusive due to the lack of an effective antiviral therapeutic molecule. The SARS-CoV-2 main protease (Mpro), which plays a vital role in the viral life cycle, is one of the most studied and validated drug targets. In Several prior studies, numerous possible chemical entities were proposed as potential Mpro inhibitors; however, most failed at various stages of drug discovery. Repositioning of existing antiviral compounds accelerates the discovery and development of potent therapeutic molecules. Hence, this study examines the applicability of anti-dengue compounds against the substrate binding site of Mpro for disrupting its polyprotein processing mechanism. An in-silico structure-based virtual screening approach is applied to screen 330 experimentally validated anti-dengue compounds to determine their affinity to the substrate binding site of Mpro. This study identified the top five compounds (CHEMBL1940602, CHEMBL2036486, CHEMBL3628485, CHEMBL200972, CHEMBL2036488) that showed a high affinity to Mpro with a docking score > -10.0 kcal/mol. The best-docked pose of these compounds with Mpro was subjected to 100 ns molecular dynamic (MD) simulation followed by MM/GBSA binding energy. This showed the maximum stability and comparable ΔG binding energy against the reference compound (X77 inhibitor). Overall, we repurposed the reported anti-dengue compounds against SARS-CoV-2-Mpro to impede its polyprotein processing for inhibiting SARS-CoV-2 infection.

Detection of Remdesivir by Liquid Chromatography with Tandem Mass Spectrometry in a Patient with SARS-CoV-2 Infection

One of the officially approved medications for the treatment of the pandemic disease COVID-19, caused by the SARS-CoV-2 virus, is remdesivir. This antiviral molecule is a prodrug that is metabolized into its active form (an ATP analogue). Because of its hepatotoxicity and nephrotoxicity, it is necessary to monitor the serum concentrations of remdesivir. For the therapeutic drug monitoring of remdesivir, a method using liquid chromatography with tandem mass spectrometry (LC-MS/MS) in positive electrospray ionization mode was developed. Mass detection was done via triple quadrupole in the Multiple reaction monitoring mode. Separation was done on Zorbax C18 column at 35 °C in mobile phase gradient and flow 0.4 mL min–1 (A – 0.1% formic acid in water, B – 0.1% formic acid in 95% acetonitrile). Time of analysis was 4 minutes. LC-MS/MS method was successfully validated. Calibration was done in blood serum and plasma and it was linear in the range of tested concentrations (0–1000 ng mL–1). Samples were prepared by protein precipitation. The method was used to measure remdesivir concentration in a patient with SARS-CoV-2 infection. The measured concentration 60 minutes after remdesivir application was 175±15 ng mL–1.

Essential Oils and COVID-19.

Herbal products are a major source of herbal medicines and other medicines. Essential oils have shown various pharmacological activities, such as antiviral activity, and therefore are proposed to have potential activity against SARS-CoV-2. Due to their lipophilicity, essential oils can easily penetrate the viral membrane and cause the viral membrane to rupture. In addition, crude essential oils usually have many active constituents that can act on different parts of the virus including its cell entry, translation, transcription, and assembly. They have further beneficial pharmacological effects on the host's respiratory system, including anti-inflammatory, immune regulation, bronchiectasis, and mucolytics. This review reported potential essential oils which could be promising drugs for COVID-19 eradication. Essential oils have many advantages because they are promising volatile antiviral molecules, making them potential drug targets for the prevention and treatment of COVID-19, whether used alone or in combination with other chemotherapeutic drugs. The aim of the current review is to shed light on the potential essential oils against enveloped viruses and their proposed activity against SARS-CoV-2 which is also an enveloped virus. The objectives were to present all data reflecting the promising activities of diverse essential oils against enveloped viruses and how they could contribute to the eradication of COVID disease, especially in indoor places. The data collected for the current review were obtained through the SciFinder database, Google scholar, PubMed, and Mendeley database. The data of the current review focused on the most common essential oils which are available in the pharmaceutical market and showed noticeable activities against enveloped viruses such as HSV and influenza.

What Is New in Prophylaxis and Treatment of COVID-19 in Renal Transplant Patients? A Report from an ESOT Meeting on the Topic

I should highlight that this manuscript is not a formal review on the topic, but a report from an ESOT meeting held on 22 June 2022. The assumption of immunosuppressants exposes kidney transplant recipients to the risk of infections, including COVID-19 infection. A transplant patient having COVID-19 infection raises several questions, including whether the immunosuppressive therapy should be reduced with the consequent risk of favoring acute rejections. Patient vaccination before transplantation is probably the gold standard to avoid the risk of COVID-19 infection after transplantation. In the case of transplant patients, three measures may be undertaken: vaccination, use of monoclonal antibodies and use of therapeutic antiviral small molecules. Concerning vaccination, it is still debated which one is the best and how many doses should be administered, particularly considering the new variants of the virus. The onset of virus variants has stimulated researchers to find new active vaccines. In addition, not all transplant patients develop antibodies. An alternative prophylactic measure to be principally used for patients that do not develop antibodies after vaccination is the use of monoclonal antibodies. These drugs may be administered as prophylaxis or in the early stage of the disease. Finally, the small antiviral molecules may be used again as prophylaxis or treatment. Their major drawbacks are their interference with immunosuppressive drugs and the fact that some of them cannot be administered to patients with low eGFR.

Reactive Centre Loop Mutagenesis of SerpinB3 to Target TMPRSS2 and Furin: Inhibition of SARS-CoV-2 Cell Entry and Replication.

The SARS-CoV-2 virus can utilize host cell proteases to facilitate cell entry, whereby the Spike (S) protein is cleaved at two specific sites to enable membrane fusion. Furin, transmembrane protease serine 2 (TMPRSS2), and cathepsin L (CatL) are the major proteases implicated, and are thus targets for anti-viral therapy. The human serpin (serine protease inhibitor) alpha-1 antitrypsin (A1AT) shows inhibitory activity for TMPRSS2, and has previously been found to suppress cell infection with SARS-CoV-2. Here, we have generated modified serpin inhibitors with increased specificity for these cellular proteases. Using SerpinB3 (SCCA-1), a cross-class inhibitor of CatL, as a scaffold, we have designed and produced reactive centre loop (RCL) variants to more specifically target both furin and TMPRSS2. Two further variants were generated by substituting the RCL P7–P1 with the spike protein S1/S2 cleavage site from either SARS-CoV-2 alpha or delta (P681R) sequences. Altered inhibitory specificity of purified recombinant proteins was verified in protease assays, with attenuated CatL inhibition and gain of furin or TMPRSS2 inhibition, as predicted, and modified serpins were shown to block S protein cleavage in vitro. Furthermore, the serpin variants were able to inhibit S-pseudoparticle entry into A549-ACE2-TMPRSS2 cells and suppress SARS-CoV-2 replication in Vero E6 cells expressing TMPRSS2. The construct designed to inhibit TMPRSS2 (B3-TMP) was most potent. It was more effective than A1AT for TMPRSS2 enzyme inhibition (with an eighteen-fold improvement in the second order inhibition rate constant) and for blocking SARS-CoV-2 viral replication. These findings advance the potential for serpin RCL mutagenesis to generate new inhibitors, and may lead to novel anti-viral biological molecules.

Assessing single-locus CRISPR/Cas9-based gene drive variants in the mosquito Aedes aegypti via single-generation crosses and modeling.

The yellow fever mosquito Aedes aegypti is a major vector of arthropod-borne viruses, including dengue, chikungunya, and Zika viruses. A novel approach to mitigate arboviral infections is to generate mosquitoes refractory to infection by overexpressing antiviral effector molecules. Such an approach requires a mechanism to spread these antiviral effectors through a population, for example, by using CRISPR/Cas9-based gene drive systems. Critical to the design of a single-locus autonomous gene drive is that the selected genomic locus is amenable to both gene drive and appropriate expression of the antiviral effector. In our study, we used reverse engineering to target 2 intergenic genomic loci, which had previously shown to be highly permissive for antiviral effector gene expression, and we further investigated the use of 3 promoters (nanos, β2-tubulin, or zpg) for Cas9 expression. We then quantified the accrual of insertions or deletions (indels) after single-generation crossings, measured maternal effects, and assessed fitness costs associated with various transgenic lines to model the rate of gene drive fixation. Overall, MGDrivE modeling suggested that when an autonomous gene drive is placed into an intergenic locus, the gene drive system will eventually be blocked by the accrual of gene drive blocking resistance alleles and ultimately be lost in the population. Moreover, while genomic locus and promoter selection were critically important for the initial establishment of the autonomous gene drive, it was the fitness of the gene drive line that most strongly influenced the persistence of the gene drive in the simulated population. As such, we propose that when autonomous CRISPR/Cas9-based gene drive systems are anchored in an intergenic locus, they temporarily result in a strong population replacement effect, but as gene drive-blocking indels accrue, the gene drive becomes exhausted due to the fixation of CRISPR resistance alleles.

Derivation, Functionalization of (S)-Goniothalamin from Goniothalamus wightii and Their Derivative Targets SARS-CoV-2 MPro, SPro, and RdRp: A Pharmacological Perspective.

The tracing of an alternative drug, Phytochemicals is a promising approach to the viral threats that have emerged over the past two years. Across the world, herbal medicine is a better solution against anti-viral diseases during pandemic periods. Goniothalamus wightii is an herbal plant, which has diverse bioactive compounds with anticancer, antioxidant, and anti-viral properties. The aim of the study was to isolate the compound by chromatography studies and functionalization by FT-IR, LC-MS, and NMR (C-NMR, H-NMR). As a result, the current work focuses on whether (S)-Goniathalamin and its analogue could act as natural anti-viral molecules for multiple target proteins viz., MPro, RdRp, and SPro, which are required for SARS-CoV-2 infection. Overall, 954 compounds were examined and the molecular-docking studies were performed on the maestro platform of Schrodinger software. Molecular-dynamics simulation studies were performed on two complex major compounds to confirm their affinity across 150 simulations. This research suggests that plant-based drugs have high levels of antiviral properties against coronavirus. However, more research is needed to verify its antiviral properties.

Phlorotannin and its Derivatives, a Potential Antiviral Molecule from Brown Seaweeds, an Overview.

Research on seaweeds provides a continual discovery of natural bioactive compounds. The review presents new information on studies of the potential and specific antiviral action of phlorotannin and their derivatives from marine brown algae. Phlorotannin is a polyphenolic derivative and a secondary metabolite from marine brown algae which exhibits a high quality of biological properties. Phlorotannin has a variety of biological activities that include antioxidant, anticancer, antiviral, anti-diabetic, anti-allergic, antibacterial, antihypertensive and immune modulating activities. These phlorotannin properties were revealed by various biochemical and cell-based assays in vitro. This distinctive polyphenol from the marine brown algae may be a potential pharmaceutical and nutraceutical compound. In this review, the extraction, quantification, characterization, purification, and biological applications of phlorotannin are discussed, and antiviral potential is described in detail.

Repurposing of potential antiviral drugs against RNA-dependent RNA polymerase of SARS-CoV-2 by computational approach

The high incidences of COVID-19 cases are believed to be associated with high transmissibility rates, which emphasizes the need for the discovery of evidence-based antiviral therapies for curing the disease. The rationale of repurposing existing classes of antiviral small molecule therapeutics against SARS-CoV-2 infection has been expected to accelerate the tedious and expensive drug development process. While Remdesivir has been recently approved to be the first treatment option for specific groups of COVID-19 patients, combinatory therapy with potential antiviral drugs may be necessary to enhance the efficacy in different populations. Hence, a comprehensive list of investigational antimicrobial drug compounds such as Favipiravir, Fidaxomicin, Galidesivir, GC376, Ribavirin, Rifabutin, and Umifenovir were computationally evaluated in this study. We performed in silico docking and molecular dynamics simulation on the selected small molecules against RNA-dependent RNA polymerase, which is one of the key target proteins of SARS-CoV-2, using AutoDock and GROMACS. Interestingly, our results revealed that the macrocyclic antibiotic, Fidaxomicin, possesses the highest binding affinity with the lowest energy value of −8.97 kcal/mol binding to the same active sites of RdRp. GC376, Rifabutin, Umifenovir and Remdesivir were identified as the next best compounds. Therefore, the above-mentioned compounds could be considered good leads for further preclinical and clinical experimentations as potentially efficient antiviral inhibitors for combination therapies against SARS-CoV-2.

Molecular Docking and Dynamic Simulation Studies of Cu(II) Metal Complexes with Covid-19 main Protease

Although the vaccine against the COVID-19 pandemic has been achieved, therapeutics still have to design to treat the infected patients. Several studies by the scientific communities are involved all over the world to develop a novel therapeutic agent against the COVID-19 virus. This study screened four β-diketone-based Cu(II) complexes against COVID-19 main protease to study their potential as an antiviral drug molecule. A molecular docking study revealed the excellent inhibitory activity of Cu(II) complexes with good binding energy values. Molecular dynamics simulation studies were carried out for 50ns to explore the selectivity profiles, conformational stability, and fluctuations of protein-ligand complexes during the simulation. Using DFT calculation, the highest occupied and lowest unoccupied molecular orbitals, electronic properties, and molecular electrostatic potential were investigated and compared with the docking results.