Editorial Current Topics in Medicinal Chemistry, 2020, Vol. 20, No.
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EDITORIAL
Effective Chemicals against Novel Coronavirus (COVID-19) in China
It is in early December 2019 a novel coronavirus was detected in Wuhan City, a city of 11 million people in Hubei Province, China, which is causing an outbreak of respiratory disease [1]. On February 11, 2020, the World Health Organization named the disease coronavirus disease 2019 (COVID- 19), which is similar to sever Middle East Respiratory Syndrome (MERS- CoV) and Severe Acute Respiratory Syndrome (SARS-CoV) in the protein sequence [2]. Now this new strain of coronavirus has subsequently spread throughout China including Hong Kong, Macao and Taiwan. As of February 22, about 76392 cases have been confirmed and over 2348 deaths in China. Now it has begun to be seen in other countries. Since the first case in the United States was confirmed on January 21, 2020 in Washington state, more than 1000 cases have been identified in 27 coun- tries including Thailand, Japan, Australia and Canada. The earliest reported cases had a link to a large seafood and animal market in Wuhan, suggesting an initial animal-to-person spread. However a growing number of subsequent patients did not expose to animal markets, indicating that a person-to-person spread is occurring [3]. This is based on what has been seen previously as the incubation period of MERS coronaviruses. The national official statistics reported the mortality of 2.01% in China. Early isolation, diagnosis and management might have col- lectively contributed to the marked reduction in mortality [4]. Furthermore, dilution of health workforce as a result of central management might have led to increased mortality rate. Currently, it is delighted to point out that at least four kinds of effective chemicals displayed strong antiviral potential which have been permitted to combat the disease in clinic according to The Sixth Edition of COVID-19 Protocol in China ( Fig. 1): lopinavir and ritonavir targeting 3CLpro; ribavirin targeting RdRp; chloro- quine diphosphate targeting endosomal acidification; arbidol targeting 2’-5’Oligoadenylates Synthesis (OAS) [5]. Lopinavir and ritonavir, belonging to a class of medications called protease inhibitors also target SARS-CoV nonstructural protein 3CLpro, were approved by FDA in 2000. During the SARS-CoV epidemic, lopinavir–ritonavir combination therapy with ribavirin in SARS patients was associated with decreased viral load and adverse clinical outcomes of death or ARDS when compared with historical control cases [6]. Shortly after the emergence of MERS, high throughput screening approaches of known antiviral compounds identified lopinavir activity against MERS-CoV in vitro [7]. Currently, at least nine clinic trials about lopinavir/ritonavir are in progress in China. The initial result suggested that lopinavir and ritonavir show exciting anti- COVID-19 activity in vivo, but with minor side effect such as diarrhea. The national expert group have recommended lopinavir and ritonavir as effective anti- COVID-19 agents in China. Ribavirin is an antiviral prescription medicine approved by FDA which is always used in combination with other drugs for the treatment of chronic Hepatitis C Virus Infection (HCV) and viral hemorrhagic fevers [8]. Producing a broad-spectrum activ- ity against several RNA and DNA viruses, ribavirin is a synthetic guanosine nucleoside that interferes with the synthesis of viral mRNA targeting RdRp. It is reported that ribavirin might be only effective in early stages of viral hemorrhagic fevers in- cluding Lasser fever, Crimean-Congo hemorrhagic fever, Venezuelan hemorrhagic fever, and Hantavirus infection. Ribavirin is a prodrug that is metabolized into nucleoside analogs that blocks viral RNA synthesis and viral mRNA capping [9]. Before the development of newer drugs, ribavirin was still considered the first-generation and standard antiviral treatment. Although ri- bavirin is not a suitable therapy for influenza, but abuse of ribavirin for viral infections is widespread in some developing coun- tries. Especially, during the SARS outbreak, China's mainland, Hong Kong, Canada and some other places have the successful experience that high doses of ribavirin in combination with antibiotics, with or without hormone to inhibit SARS-CoV [10]. Currently, it appears that ribavirin in combination with interferon or lopinavi /ritonavir is still effective means to treat COVID- 19 infection. Chloroquine, introduced into medicine in the 1940s, is a member of an important series of chemically related antimalarial agents, the quinoline derivatives. Chloroquine phosphate is administered orally as chloroquine derivative. Chloroquine phos- phate locates in a class of drugs called antimalarials and amebicides which is used to prevent and treat malaria. Also, chloro- quine phosphate is applied to decrease the symptoms of rheumatoid arthritis and treat systemic and discoid lupus erythemato- sus, scleroderma, pemphigus, lichen planus, polymyositis, sarcoidosis, and porphyria cutanea tarda. In consideration of chloro- quine phosphate in clinic for decades, it is with the advantage of known and rarely-occurring adverse reactions. Based on the advantage of elicit antiviral effects against several viruses, including SARS-CoV and HCoV-229E [11], as soon as COVID-19 spread in China, researchers from Wuhan Institute of Virology evaluated the antiviral efficiency of chloroquine against a clini- cal isolate of 2019-nCoV in vitro, and they found that it was highly effective in the control of 2019-nCoV infection [12]. Fol- lowingly, a series of clinic trials about chloroquine phosphate have been moved in a rapid speed. Now chloroquine phosphate has been used to treat adult patient suffering from the novel coronavirus disease.
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Arbidol, a small monocular compound, is used to prevent severe pneumonia and virus-associated cytokine dysregulation which has been administered for decades in Russia and China, with no major adverse effects reported [13]. Its vast potential as a broad-spectrum antiviral agent, defined through in vitro and in vivo studies, lends hope for its clinical use against various in- fectious diseases that are at present not therapeutically controlled. In addition to influenza and pathogenic human respiratory viruses, arbidol shows mainly in vitro inhibitory activity against the Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Chi- kungunya Virus (CHIKV), reovirus, Hantaan virus and coxsackie virus B5. Arbidol inhibits viral entry into host cell and stimu- lates immune response. And more, it could inhibit fusion between the viral capsid and the cell membrane of the target cell, thus preventing viral entry [14]. Recently, Pro. Li from China reported that arbidol displayed potent anti-COVID-19 activity in con- trast to the control with IC50 from 10 to 30 μM. Soon after that, arbidol has been regarded as the initial therapy against COVID- 19. In addition to four kinds of chemicals approved against COVID-19, at least another three molecules are in clicnic trial with promising activity in vivo: both remdesivir and favipiravir against RdRp; darunavir against 3CLpro. Especially remdesivir that cured the first case of 2019-nCoV infection confirmed in the United States, hold great expectations for 2019-nCoV therapy [15]. Lastly, it is worthy to note that preclinical safety evaluation and complete clinic trials (phase I~IV) are still necessary for drug's launch after the end of virus outbreak.
Fig. (1). Four kinds of chemicals approved against COVID-19 in China.
FUNDING This work was supported by the China Postdoctoral Science Foundation (No. 2019M652586), Postdoctoral Research Grant in Henan Province (Nos. 1902001 and 19030008) and Henan Medical Science and Technology Program (2018020601).
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Wei Liu, Hai-liang Zhu* and Yongtao Duan*
(Guest Editors) Current Topics in Medicinal Chemistry Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases Children's Hospital Affiliated to Zhengzhou University Zhengzhou, 450018 China *E-mails: duanyongtao860409@163.com; zhuhl@nju.edu.cn
