International Journal of Molecular Sciences Review The Current Status of Drug Repositioning and Vaccine Developments for the COVID-19 Pandemic Jung-Hyun Won 1,2 and Howard Lee 1,2,3,4,5,* 1 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Korea; [email protected] 2 Center for Convergence Approaches in Drug Development, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Korea 3 Department of Clinical Pharmacology and Therapeutics, College of Medicine, Seoul National University, Seoul 03080, Korea 4 Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul 03080, Korea 5 Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 16229, Korea * Correspondence: [email protected]; Tel.: +82-2-3668-7602; Fax: +82-2-742-9252 Received: 30 November 2020; Accepted: 18 December 2020; Published: 21 December 2020 Abstract: Since the outbreak of coronavirus disease 2019 (COVID-19) was first identified, the world has vehemently worked to develop treatments and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at an unprecedented speed. Few of the repositioned drugs for COVID-19 have shown that they were efficacious and safe. In contrast, a couple of vaccines against SARS-CoV-2 will be ready for mass rollout early next year. Despite successful vaccine development for COVID-19, the world will face a whole new set of challenges including scale-up manufacturing, cold-chain logistics, long-term safety, and low vaccine acceptance. We highlighted the importance of knowledge sharing and collaboration to find innovative answers to these challenges and to prepare for newly emerging viruses. Keywords: SARS-CoV-2; COVID-19; drug repositioning; vaccine; public health crisis 1. Introduction The outbreak of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first reported in Wuhan City, Hubei Province, China, on 31 December 2019, has spread over the world with an unparalleled speed [1,2]. The disease is so transmissible that the number of cases and deaths rose rapidly across borders, which prompted the World Health Organization (WHO) to declare the COVID-19 outbreak to be a global pandemic on 11 March 2020. As of 26 November 2020, more than 60,700,000 cases and 1,425,000 deaths have been reported worldwide [3]. Given the severity of the disease and the rapid rise in the number of affected individuals, therapeutics and vaccines to tackle COVID-19 are urgently needed. Scientists, governments, regulators, and pharmaceutical companies from every corner of the globe have ramped up together to develop drugs and vaccines against SARS-CoV-2 [4]. However, the therapeutic strategies to cope with SARS-CoV-2 infection have only played a supportive role until now [5]. Initially, the repositioning of existing drugs received much attention because it could be a short-cut compared with conventional, lengthy, and costly new drug development, but its effectiveness has not been satisfactory yet [6]. Therefore, prevention which aimed to reduce transmission while establishing a herd immunity using vaccines seems to be the key to ending the COVID-19 pandemic. Int. J. Mol. Sci. 2020, 21, 9775; doi:10.3390/ijms21249775 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 9775 2 of 17 Vaccines against SARS-CoV-2 are being developed on an unprecedented fast track [4,7,8]. However, even if vaccines are successfully developed, there are still many questions with definitive answers that are unavailable. For example, how can we efficiently manufacture at least 16 billion doses of vaccine to cover the entire world assuming two doses are needed for each person, how will the vaccines be distributed to people in need with their quality being unaffected (i.e., when using cold-chain methods), and how are we going to raise public awareness of the vaccine and its necessity? Furthermore, vaccines may come too late to influence the first wave of the pandemic, although they might be useful for next waves and for a post-pandemic scenario. Certainly, humankind will learn important lessons from handling the global pandemic at this scale, which will allow us to be better prepared for the future public health crises. The objectives of this review were three-fold. First, we briefly summarized up-to-date published clinical data of leading drug repositioning options and vaccine developments for COVID-19. Second, we discussed remaining challenges and issues we will face after a vaccine is successfully developed. Third, we stressed the importance of innovative, well-coordinated, long-term research to prepare for future public health crises. To better achieve those objectives, we first briefly described the characteristics of the coronavirus. 2. Coronavirus in Brief The coronavirus is a positive single-stranded RNA virus (+ssRNA) with a crown-like appearance [9]. Viruses of the family Coronaviridae have been identified in, but not limited to, mammals, including mice, dogs, bats, and cats [10]. To date, several novel mammalian coronaviruses such as SARS (severe acute respiratory syndrome) and MERS (middle east respiratory syndrome) have been shown to be pathogenic to humans [10]. SARS-CoV-2 is a novel coronavirus belonging to the betaCoVs category [11]. SARS-CoV-2 is highly related to two bat-derived SARS viruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21 with an 88% overlap of genome sequences [11]. SARS-CoV-2 also showed 79% and 50% overlap of genome sequences with SARS-CoV and with MERS-CoV, respectively [11]. Besides, the pangolin coronavirus, i.e., pangolin-CoV-2020, showed 90.32% overlap of its genome sequence with SARS-CoV-2 [12]. The genome of SARS-CoV-2 encodes the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins (Figure1)[ 13]. The genomic sequence of SARS-CoV-2 encoding the S protein was highly related to the Bat-CoV-RaTG13 and pangolin-CoV-2020 with 93.15% and 84.52% overlap, respectively [12]. Each protein has its own functions, of which the spike and the envelope proteins have a pivotal role in virus pathogenicity. For example, the spike protein mediates viral invasion into hostInt. J. cellsMol. Sci. via 2020 the, 21 angiotensin-converting, x FOR PEER REVIEW enzyme 2 (ACE2), and the envelope protein is involved3 in of the 18 formation and release of viral particles [13]. Figure 1. Structure of human coronavirus: the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. Created with BioRender (https://biorender.com/)[13]. Figure 1. Structure of human coronavirus: the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. Created with BioRender (https://biorender.com/) [13]. ACE2 is expressed in the bronchus, lung, heart, nasal mucosa, etc. [14]. When SARS-CoV-2 enters the respiratory tract, where ACE2 receptor binding sites are highly expressed, SARS-CoV-2 first binds to ACE2 and penetrates into the target cell [15]. Next, viral RNA is replicated by the RNA- dependent RNA polymerase (RdRp), and various viral proteins required to infect the host are produced by using the viral RNA [15]. A complete structure of SARS-CoV-2, composed of those replicated RNA and proteins, leaves the infected cell and eventually spreads throughout the body through successive proliferation (Figure 2) [15]. Figure 2. Viral entry mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 first binds to ACE2 expressed in nasal epithelial cells or the respiratory tract and then penetrates into the target cell. Created with BioRender (https://biorender.com/) [16]. Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 18 Figure 1. Structure of human coronavirus: the spike (S), envelope (E), membrane (M), and Int. J. Mol. Sci. 2020, 21, 9775 3 of 17 nucleocapsid (N) proteins. Created with BioRender (https://biorender.com/) [13]. ACE2 isis expressedexpressed in in the the bronchus, bronchus, lung, lung, heart, heart, nasal nasal mucosa, mucosa, etc. [14etc.]. When[14]. When SARS-CoV-2 SARS-CoV-2 enters entersthe respiratory the respiratory tract, where tract, ACE2where receptor ACE2 receptor binding sitesbinding are highlysites are expressed, highly expressed, SARS-CoV-2 SARS-CoV-2 first binds firstto ACE2 binds and to ACE2 penetrates and penetrates into the target into cellthe [target15]. Next, cell [15]. viral Next, RNA viral is replicated RNA is replicated by the RNA-dependent by the RNA- dependentRNA polymerase RNA (RdRp),polymerase and various(RdRp), viraland proteinsvarious requiredviral proteins to infect required the host to are infect produced the host by using are producedthe viral RNA by using [15]. the A complete viral RNA structure [15]. A ofcomplete SARS-CoV-2, structure composed of SARS-CoV of those-2, replicated composed RNA of those and replicatedproteins,leaves RNA and the infectedproteins, cell leaves and the eventually infected spreadscell and throughouteventually spreads the body throughout through successive the body throughproliferation successive (Figure proliferation2)[15]. (Figure 2) [15]. Figure 2. Viral entry mechanism of of severe severe acute acute respiratory respiratory syndrome syndrome coronavirus coronavirus 2 2 (SARS-CoV-2). (SARS-CoV-2). SARS-CoV-2 first first binds to ACE2 expressed in nasal epithelial cells or the respiratory tract and then penetrates into the target cell. Created with BioRender (https://biorender.com/)[16]. penetrates into the target cell. Created with BioRender (https://biorender.com/) [16]. 3. Drug Repositioning for SARS-CoV-2 Infection At the time of writing this review, few treatments have been proven to be efficacious against SARS-CoV-2 infection. According to a living WHO guideline on drugs for COVID-19, many treatments against SARS-CoV-2 infection are only supportive and symptomatic, for example, ventilation, corticosteroids such as dexamethasone, and immunomodulatory drugs [5].