Abstract
SARS-CoV-2 has been marked as a highly pathogenic coronavirus of COVID-19 disease into the human population, causing over 2.8 million confirmed cases worldwide. As COVID-19 has posed a global threat with significant human casualties and severe economic losses, there is a pressing demand to further understand the current situation and develop rational strategies to contain the drastic spread of the virus. Although there are no specific antiviral therapies that have proven effective in randomized clinical trials, currently, the rapid detection technology along with several promising therapeutics for COVID-19 have mitigated its drastic transmission. Besides, global institutions and corporations have commenced to parse out effective vaccines for the prevention of COVID-19. Herein, the present review will give exhaustive details of extensive researches concerning the drug discovery and therapeutic options for COVID-19 as well as some insightful discussions of the status of COVID-19.
Key word: coronavirus, COVID-19, SARS-CoV-2, precise prevention and control, drug discovery, vaccine development
Introduction
This century has witnessed the worldwide spread of several hitherto unknown coronaviruses. The rapid alteration of ecology and urbanization along with vulnerable public health systems have facilitated more frequent emerging of epidemics, which have become more and more intractable for us to prevent and contain. In December 2019, a new coronavirus correlated with human respiratory disease was firstly reported causing pneumonia and death (Chan et al., 2020b). Soon afterward, the disease cases continued to expand and soared dramatically worldwide. The causative virus, named as SARS-CoV-2, was identified as the pathogen leading to the coronavirus disease COVID-19. Infections with SARS-CoV-2 are now swift and violent, and as of 26 April 2020, over 2.8 million cases have been confirmed in more than 207 countries, with over 193,825 deaths. To date, SARS-CoV-2 has most closest relation to SARS and relevant viruses that circulate in bats, as evidenced by viral genome analysis as well as the research probing into the proximal origin of such virus (Andersen et al., 2020).
In general, coronaviruses (CoVs), subfamily Coronavirinae, are a cluster of highly diversified, enveloped, positive-sense, single-stranded viruses ((+)ssRNA virus) that can induce enteric, respiratory, hepatic as well as neurological disorders of discrepant severity in a wide range of animal species, encompassing humans (Chan et al., 2013; Zumla et al., 2016). As the largest RNA viruses ever discovered, CoVs can be categorized into α-, β-, δ- and γ-coronaviruses. Among these genera, the β group can be subdivided into A, B, C, and D lineages (Xia et al., 2020b). In the past 17 years, three neoteric β-CoVs, severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), along with SARS-CoV-2 have emerged, engendering severe human diseases. Although the origin of the SARS-CoV-2 outbreak is not yet clear, recent studies have deduced that it might be transmitted through bats because it is highly similar to the bat SARS-CoV-like coronaviruses (Zhou et al., 2020b). Later on, genomic and evolutionary proofs of the occurrence of Pangolin-CoV indicated that pangolin species might be the potential intermediate host for SARS-CoV-2 (Cyranoski, 2020; T. Zhang et al., 2020). Unlike human coronaviruses, zoonotic viruses hold the capacity of infecting both animals and humans, leading to severe respiratory diseases (i.e., acute respiratory distress syndrome (ARDS) and pneumonia)(Graham et al., 2013; Peiris et al., 2003). Clinical data revealed that the COVID-19 symptoms are far more severe among the elders with comorbidities, while asthma, allergic illnesses, as well as chronic obstructive pulmonary disease are also risk factors (X. Yang et al., 2020; J. Zhang et al., 2020). Despite the continuous improvement of the prevention strategy and the disease surveillance system, the lack of efficacious drug treatment and correlated high morbidity cases of the SARS-CoV-2 along with its potentiality to induce pandemics, highlighting the urgent demand for neoteric drug discovery. In this review, we will first briefly describe the status of epidemiology, mechanism, and diagnosis of COVID-19. In addition to the discussion of current management strategies for COVID-19, the emphasis has been given to the treatment options and drug discovery of COVID-19. We will refer to the drug screening progress and the development of vaccines for the COVID-19 therapy. Ultimately, we will delineate the overarching challenges in the clinical invention of new anti-coronavirus agents and offer some insights toward the prevention of such disease based on the understanding of its epidemic dynamics in real-time.
The epidemiology of COVID-19
Spread mainly through respiratory droplets or close contact, SARS-CoV-2 induced diseases has been growing dramatically in accordance with the published data from the World Health Organization (WHO) (Organization, 2020). Although the number of confirmed cases in China has decreased a lot from late February 2020, and there is no report of COVID-19 deaths on 6 April, the confirmed cases of coronavirus worldwide are still expanding with a vengeance. The spectrum of illness presentation or severity profile also affects triage and diagnostic decision-making, along with the therapeutic options and prognostic expectations (Wu et al., 2020c). Till now, the exact source of the current outbreak of COVID-19 remains unclear, but the dynamic model is similar to the classic zoonotic emergence to human-to-human transmission (Metcalf and Lessler, 2017). The mortality rate of SARS-CoV-2 (~3.8%) is lower compared to that of MERS-CoV (37.1%) or SARS-CoV (10%), but the number of infections is more than ten times higher (Ahn et al., 2020). With respect to the lack of evidence that companion animals might be a source of infection, patients with COVID-19 are the prime source of infection, and those with severe conditions are more infectious than those with mild conditions. Intriguingly, asymptomatically infected persons or patients in incubation has also been demonstrated to shed the infectious virus, serving as a potential infection source to drive the transmission of the COVID-19 (Hoehl et al., 2020). In addition, researches focused on the follow-up of recovered patients revealed that the tested samples of rehabilitees continuously showed a positive RT-PCR result, implicating that asymptomatic infection during incubation or recovery from COVID-19 may pose a daunting challenge to disease control and prevention (Lan et al., 2020).
The incubation period refers to the time between exposure to the virus and initial symptoms. A research report on the early propagation dynamics of COVID-19 unveiled that the average incubation period of COVID-19 was around 5 days, and its 95% distribution was 12.5 days (Li et al., 2020). Another study analyzing the travel history and symptoms in 88 confirmed cases revealed a similar average incubation period of around 6 days (Backer et al., 2020). In addition, there was an unusual case with an incubation period of up to 19 days (Bai et al., 2020). Although such a long incubation period may be a low probability event (the condition of 14 days was suggested by experts for quarantine), the longer incubation time indicates the adjustment of screening and control policies (Jiang et al., 2020).
The early outbreak data of COVID-19 largely follow exponential growth. Disparate models based upon the clinical progression of the disease had been proposed to assess the basic reproductive ratio R0. A retrospective analysis of the first 425 identified cases demonstrated that in the early stages of COVID-19, the R0 was assessed to be 2.2 (Li et al., 2020). Nevertheless, deterministic compartmental models based upon the likelihood and a model analysis revealed that the control reproduction number Rc might be as high as 6.5 due to the estimation of four generations of viral transmission and serried social contacts (Tang et al., 2020). In this regard, it is noteworthy that R0 estimates may vary in the light of numerous biologics, social behavior, and environmental factors (Delamater et al., 2019). In general, the basic R0 assessed by the majority of researches ranges between 2 to 4 (Lai et al., 2020). According to the WHO data updated on April 26, 2020, more than 200 countries have reported 2,810,325 confirmed cases, including 193,825 deaths (Figure 1). The grand total case fatality rate of global cases outside China is 2.39% (WHO, 2020). The US had also recorded the largest number of coronavirus deaths in a day, with more than 1,810 deaths reported on April 7, according to data from Johns Hopkins University. Given the condition that the population of all races and ages is generally susceptible, there is an urgent need to further implementing the timely diagnosis, along with efficient isolation of patients, to cut down the R0 of SARS-CoV-2 and control the epidemic outbreak.