key: cord-336561-llwjsds8 authors: Ghosh, Sanhita; Firdous, Sayeed Mohammad; Nath, Anirban title: siRNA could be a potential therapy for COVID-19 date: 2020-04-22 journal: EXCLI J DOI: 10.17179/excli2020-1328 sha: doc_id: 336561 cord_uid: llwjsds8 nan teases, namely papain-like protease (nsp3) and the main protease designated as 3-chymotrypsin-like protease or 3CL. Among two viral proteases the sequence which codes for the nsp3 has been reported to be less conserved . However, the sequence which codes for the protease 3CL (nsp5) has been observed to be highly conserved among the annotated sequences (Wu et al., 2020b) . Currently, the protease has been considered as a major drug target for multiple antiviral agents, which are presently undergoing clinical trials. Thus, the sequence coding for nsp5 can be treated as a potential target for RNAi using siRNA based therapeutics. Other potential targets include the viral RNA dependent RNA polymerase (Rd-Rp) which is located in the ORF1b, stretching from 13-16 kbp on the viral genome. Downstream to the sequences (from 16-18 kbp) the site coding for the viral helicase has been identified. These two sites have been reported to be highly conserved among the annotated genome of SARS-CoV-2 along with the earlier genomes of beta coronaviruses like SARS and MERS (Wu et al., 2020b) . Thus, these two sites can be considered to be potential targets for RNAi using siRNA. To date, various delivery systems for siRNA have been identified which are broadly classified into nanoparticles based carriers and viral vectors. In 2003, siRNA based drug was developed by Sirnaomics, Inc. (Maryland, USA) for the outbreak of SARS-CoV and H5N1 influenza. Besides, in 2017, six siRNA have been developed by Alnylam Pharmaceuticals (USA) and Vir Biotechnology against infectious diseases. Further, Alnylam Pharmaceuticals (USA) has designed and synthesized over 350 siRNA targeting highly conserved regions of the available SARS-CoV-2 genome (Hodgson, 2020) . However, effective carriers must be identified for the successful delivery of the drug payload at the areas which are predominantly infected by the pathogen. For SARS-CoV-2, the ciliated cells of the human lungs are the primary site for viral infection, with reports indicating viral transmission via contact, droplets of saliva or fomites from the infected person. Therefore, techniques designed for optimal delivery of drugs onto the lung epithelial cells can provide better and timely results. In this context, Conti and co-researchers have demonstrated an in vitro testing of poly (amidoamine) dendrimer nanocarriers for the potential aerosol-based delivery system of siRNA onto lung epithelial cells (Conti et al., 2014) . However, the nanocarrier delivery system has limits to its efficient delivery. Hence, there is a need to overcome these limitations by formulating an effective delivery system that can offer unique advances to the field of inhaled siRNA formulation. Despite the pandemic outbreaks of COVID-19 and the high rate of transmission in humans, there is no specific treatment for the COVID-19 at present. Thus, for the treatment of COVID-19 siRNA based therapy can be developed against the novel coronavirus SARS-CoV-2, where siRNAs can hit the highly conserved region of SARS-CoV-2 RNA and also can act as an inhibitor to suppress the genetic disorders of the lungs. This approach could help to achieve a better treatment goal that can reduce the pandemic threat of COVID-19. The invention describes the development of double-stranded siRNA analogs that contain locked nucleic acid (LNA), which showed a specific post-transcriptional gene silencing by RNAi. These siRNAs can be useful to target the SARS gene. The cytopathic effect (CPE) was observed in Vero cells when it was infected with SARS and reduced the CPE after siRNA treatment. Besides, the invention describes the inhibition of SARSinduced cytotoxicity by siRNA. https://patents.google.com/patent/US8653252 Poly (amidoamine) dendrimer nanocarriers and their aerosol formulations for siRNA delivery to the lung epithelium Short interfering RNA (siRNA) analogues The pandemic pipeline Online ahead of print Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases SARS coronavirus disturbance RNA and its uses RNAi agents for anti-SARS coronavirus therapy Small interfering RNA for restraining SARS corona virus M protein gene expression, encoding gene and application thereof Medicine for preventing and treatig SARS coronavirus WHO Coronavirus disease (COVID-2019) situation reports. Geneva: WHO Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China A new coronavirus associated with human respiratory disease in China siRNA disturbing RdRp gene function of SARS virus The authors declare no conflict of interest.