2020 was a pandemic year in human civilization that has affected 220 countries and resulted in 1.4 million deaths so far. This pandemic was the outcome of infection caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) that accounted for 63 million confirmed human infections (World Health Organization (WHO)). The highly pathogenic virus strain was first reported in Wuhan, China in December 2019 leading to coronavirus disease 2019 (COVID-19). Highly pathogenic SARS- CoV2 is an enveloped, single-stranded RNA virus of Coronaviridae family, which encode non-structural proteins (nsps), structural proteins, and several accessory proteins. Being a respiratory virus, primarily transmitted through aerosol and contact, it affected mainly the respiratory tract but Brain, Liver and Kidney have also been reported to be secondarily damaged. To fight the pandemic an effective vaccine or drug is urgently needed. Several licensed coronavirus (CoV) vaccines are available for domestic animals but not for humans. Two vaccine candidates for SARS- CoV and three for MERS- CoV are in phase I clinical trials (WHO). A successful vaccine must elicit both humoral and cellular immunity with immunologic memory. It must evoke immune response within the incubation period. Also, it must evoke humoral response against conserved coat proteins. However, an improper vaccine has potential risks of enhancement of the disease through antibody- dependent enhancement (ADE) mediated by non-neutralizing virus binding antibodies or enhanced respiratory disease (ERD) mediated by our own biased immune cell T helper 2 (TH2). It must be noted that already infected patients must be given specific drugs to get rid of the virus and vaccines have no use for them. Vaccines provide life-long immunity to normal uninfected persons through repeated exposure by developing immunologic memory. All CoV enzymes and proteins involved in viral replication and the control of host cellular machineries are potential drug targets to be used as therapeutic agents for SARS- CoV-2. There are a number of drugs with activity, currently being investigated against virus-based and host-based targets. Vaccines for SARS- CoV-2 Out of more than 214 COVID-19 vaccines, 51 are in clinical trials, 13 of them in phase III trials and several ready for field use (WHO; COVID-19 Vaccine tracker). There are three broad categories of candidate vaccines – first, protein- based vaccines such as inactivated virus vaccines, virus- like particles and protein subunit vaccines; second, gene- based vaccines such as virus- vectored vaccines, DNA vaccines and mRNA vaccines; and, third, a combination of both protein- based and gene- based vaccines such as live- attenuated virus vaccines. Hence, seven types of vaccines are being evaluated for potential use against COVID-19. These are summarized in the following table: Vaccine targets of SARS- CoV-2 SARS- CoV-2 encodes four structural (spike (S), membrane (M), envelope (E) and nucleocapsid (N)), 16 non-structural (nsp1-16) and 9 accessory proteins. All of these are potentially immunogenic and may be used to generate vaccines. However, S protein is the main target for vaccine development as it is involved in host cell receptor binding and membrane fusion and it’s a large protein having highly immunogenic epitopes. Thirteen vaccines against “S” protein are currently being developed and out of them 8 are in Phase III trials like Oxford-AstraZeneca, Moderna, BioNTech-Pfizer, Novavax, Janssen etc. These vaccines use full length S protein with or without some substitutions or the receptor binding domain (RBD) as immunogen. Unlike S protein, M and E are poorly immunogenic due to their small molecular size. Hence, no vaccine is currently being developed using these proteins. On the other hand N protein is highly immunogenic but it has been reported that vaccine expressing N protein enhanced infection- induced pneumonia and ERD. Other than targeting a specific protein, whole UV, heat or chemically inactivated viruses are also being used to generate vaccines. Inactivated viruses contain all structural coat proteins, hence, they induce a broader antibody and T cell responses. Currently 4 inactivated virus vaccines are being developed and 3 of them are in phase III clinical trials (Sinovac, Sinopharm etc.). Drugs for SARS- CoV-2 Structure-based therapeutic drugs are being designed (some with computational studies) against SARS- CoV-2 structural (S, E, M and N) and non-structural (nsp1-16) proteins and also against host proteins that are crucial for virus life cycle. These proteins are pharmacological targets of specific therapeutic compounds or ligands due to their critical function in viral transcription and replication. Drugs inactivate specific proteins by binding with specific amino acids or domains on them. Several drugs, effective against other diseases, are currently being analyzed and considered or repurposed in CoV treatment. Following table represents drug targets with experimentally potential compounds against CoV proteins— Some of these potential drugs are in clinical trials for their efficacy. Apart from targeting key viral proteins, host cell factors are also being analyzed as potential drug targets to curb infection. These host factors regulate viral entry and inflammatory responses. Some of the anti-host drugs are under clinical trials – Some drugs have already been proven effective in clinical trials and got approval like Galidesivir, Chlorpromazine, Triflupromazine, Resveratrol, Gemcitabine, Mefloquine, Loperamide, Ivermectin, Losartan, Chloroquine, and Hydroxycholoquine. Finally, it should be noted that combination therapeutic approach is more promising to evade viral mutation escape. Though drug repurposing giving hope, an effective vaccine and novel multi-targetable drugs must be developed for current as well as future epidemic re-emergence. References: Bloch, E. M. et al. J. Clin. Invest. 130, 2757–2765 (2020).Burrage, D. R., Koushesh, S. & Sofat, N. Front. Immunol. 11, 1844 (2020).Cai, Y. et al. Science 369, 1586–1592 (2020).Chi, X. et al. Science 369, 650–655 (2020).Dai, L., Gao, G.F. Nat. Rev. Immunol. (2020).Fung, M. et al. Transpl. Infect. Dis.(2020).Gao, Q. et al. Science 369, 77–81 (2020).Gil, C. et al. J. Med. Chem. 63, 12359−12386 (2020).Graham, B. S. Science 368, 945–946 (2020).Hueso, T. et al. Blood 136, 2290–2295 (2020).Le, T. T. Nat. Rev. Drug. Discov. 19, 305-306 (2020).Lee, W. S., Wheatley, A. K., Kent, S. J. & DeKosky, B. J. Nat. Microbiol. 5, 1185–1191 (2020).Liu, X., Cao, W. & Li, T. Front. Immunol. 11, 1660 (2020).McKee, D. L. et al. […]
One Comment on “#462 Discipline – S2 E6 – The Process – Why routines work”
Wow that was strange. I just wrote an really long comment but after I clicked submit my comment didn’t show up. Grrrr… well I’m not writing all that over again. Anyways, just wanted to say superb blog!
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