Nanotechnology Integration for SARS-CoV-2 Diagnosis and Treatment: An Approach to Preventing Pandemic

The SARS-CoV-2 outbreak is the COVID-19 disease, which has caused massive health devastation, prompting the World Health Organization to declare a worldwide health emergency. The corona virus infected millions of people worldwide, and many died as a result of a lack of particular medications. The current emergency necessitates extensive therapy in order to stop the spread of the coronavirus. There are various vaccinations available, but no validated COVID-19 treatments. Since its outbreak, many therapeutics have been tested, including the use of repurposed medications, nucleoside inhibitors, protease inhibitors, broad spectrum antivirals, convalescence plasma therapies, immune-modulators, and monoclonal antibodies. However, these approaches have not yielded any outcomes and are mostly used to alleviate symptoms associated with potentially fatal adverse drug reactions. Nanoparticles, on the other hand, may prove to be an effective treatment for COVID-19. They can be designed to boost the efficacy of currently available antiviral medications or to trigger a rapid immune response against COVID-19. In the last decade, there has been significant progress in nanotechnology. This review focuses on the virus’s basic structure, pathogenesis, and current treatment options for COVID-19. This study addresses nanotechnology and its applications in diagnosis, prevention, treatment, and targeted vaccine delivery, laying the groundwork for a successful pandemic fight.

Novel non-nucleoside inhibitors of Zika virus polymerase identified through the screening of an open library of anti-kynetoplastid compounds

Zika virus (ZIKV) is a mosquito-borne pathogen responsible for neurological disorders (Guillain-Barré syndrome) and congenital malformations (microcephaly). Its ability to cause explosive epidemics, such as that of 2015-16, urges the identification for effective antiviral drugs. Viral polymerase inhibitors constitute one of the most successful fields in antiviral research. Accordingly, the RNA-dependent RNA polymerase activity of flavivirus NS5 protein provides a unique target for the development of direct antivirals with high specificity and low toxicity. Here we describe the discovery and characterization of two novel non-nucleoside inhibitors of ZIKV polymerase. These inhibitors, TCMDC-143406 ( 6 ) and TCMDC-143215 ( 15 ), were identified through the screening of an open resource library of anti-kinetoplastid compounds using a fluorescence-based polymerization assay based on ZIKV NS5. The two compounds inhibited ZIKV NS5 polymerase activity in vitro and ZIKV multiplication in cell culture (EC 50 values of 0.5 and 2.6 μM for 6 and 15 , respectively). Both compounds also inhibited the replication of other pathogenic flaviviruses, namely West Nile virus (WNV; EC 50 values of 4.3 and 4.6 μM for 6 and 15 , respectively) and dengue virus 2 (DENV-2; EC 50 values of 3.4 and 9.6 μM for 6 and 15 , respectively). Enzymatic assays confirmed that the polymerase inhibition was produced by a non-competitive mechanism. Combinatorial assays revealed an antagonistic effect between both compounds, suggesting that they would bind to the same region of ZIKV polymerase. The non-nucleoside inhibitors of ZIKV polymerase here described could constitute promising lead compounds for the development of anti-ZIKV therapies and eventually broad-spectrum anti-flavivirus drugs.

Nucleoside Inhibitors of Coronaviruses

Coronaviruses (CoVs) belong to a large family of zoonotic supercapsid viruses, including about 40 species of RNA-containing viruses with several strains capable of causing damage to the lungs and respiratory tract. The severe acute respiratory syndrome coronavirus (SARS-CoV) was responsible for the worldwide SARS outbreak in 2003. The rapid global spread of SARS-CoV-2 has been the cause of significant health concern and thousands of deaths in 2019−2020 and outlined the need for novel antivirals. The present review is devoted to the development of effective and selective nucleoside drugs for the treatment of coronavirus infections. To date, about half of antivirals have been created based on nucleosides. The majority of drugs based on nucleosides have been approved by FDA. This indicates a fruitful area for the development of novel antivirals based on nucleosides. The review describes the main features of pathogenic SARS-CoV, MERS-CoV, and SARS-CoV-2 strains, presents their comparison, considers promising approaches to creating nucleoside drugs for the treatment of coronavirus infections, and provides a systematic evaluation of all the known nucleoside derivatives, which inhibit the reproduction of coronaviruses in cells. To date, two known nucleoside drugs (Ribavirin, Favipiravir) have been recommended for the treatment of SARS-CoV-2 infection and nine hit compounds based on nucleosides and their analogues have been found, one of which efficiently suppressing SARS-CoV-2 replication and eight others inhibiting SARS-CoV replication.

Design and Optimization of Quinazoline Derivatives: New Non-nucleoside Inhibitors of Bovine Viral Diarrhea Virus

Bovine viral diarrhea virus (BVDV) belongs to the Pestivirus genus (Flaviviridae). In spite of the availability of vaccines, the virus is still causing substantial financial losses to the livestock industry. In this context, the use of antiviral agents could be an alternative strategy to control and reduce viral infections. The viral RNA-dependent RNA polymerase (RdRp) is essential for the replication of the viral genome and constitutes an attractive target for the identification of antiviral compounds. In a previous work, we have identified potential molecules that dock into an allosteric binding pocket of BVDV RdRp via a structure-based virtual screening approach. One of them, N-(2-morpholinoethyl)-2-phenylquinazolin-4-amine [1, 50% effective concentration (EC50) = 9.7 ± 0.5 μM], was selected to perform different chemical modifications. Among 24 derivatives synthesized, eight of them showed considerable antiviral activity. Molecular modeling of the most active compounds showed that they bind to a pocket located in the fingers and thumb domains in BVDV RdRp, which is different from that identified for other non-nucleoside inhibitors (NNIs) such as thiosemicarbazone (TSC). We selected compound 2-[4-(2-phenylquinazolin-4-yl)piperazin-1-yl]ethanol (1.9; EC50 = 1.7 ± 0.4 μM) for further analysis. Compound 1.9 was found to inhibit the in vitro replication of TSC-resistant BVDV variants, which carry the N264D mutation in the RdRp. In addition, 1.9 presented adequate solubility in different media and a high-stability profile in murine and bovine plasma.

Potential Inhibition of COVID-19 RNA-dependent RNA Polymerase by Hepatitis C Virus Non-nucleoside Inhibitors: An In-silico Perspective

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel member of the genus betacoronavirus in the Coronaviridae family. It has been identified as the causative agent of coronavirus disease 2019 (COVID-19) spreading rapidly in Asia, America and Europe. Like some other RNA viruses, RNA replication and transcription of SARS-CoV-2 relies on its RNA-dependent RNA polymerase (RdRP), which is a therapeutic target of clinical importance. Crystal structure of SARS-CoV-2 that was solved recently (PDB ID 6M71) with some missing residues. Objective: We used SARS-CoV-2 RdRP as a target protein to screen for possible chemical molecules with potential antiviral effects. Method: Here we modelled the missing residues 896-905 via homology modelling and then analysed the interactions of Hepatitis C virus allosteric non-nucleoside inhibitors (NNIs) in the reported NNIs binding sites in SARS-CoV-2 RdRP. Results and Discussion: We found that MK-3281, filibuvir, setrobuvir and dasabuvir might be able to inhibit SARS-CoV-2 RdRP based on their binding affinities in the respective binding sites. Conclusion: Further in vitro and in vivo experimental research will be carried out to evaluate their effectiveness in COVID19 treatment in the near future.