European Review for Medical and Pharmacological Sciences 2021; 25: 541-548 Remdesivir as a broad-spectrum against COVID-19

Y.-N. HONG1, J. XU1, G.B.K. SASA1, K.-X. ZHOU2, X.-F. DING1

1Zhejiang Sci-Tech University, Zhejiang, HangZhou, China 2Xixi Hospital of HangZhou, Zhejiang, HangZhou, China

Abstract. – OBJECTIVE: List the clinical data of Based on the virological classification, Corona- the role of remdesivir in COVID-19, and try to make viruses (CoVs) belong to the subfamily of Corona- an objective evaluation and analyze its feasibility. virinae, which includes four genera: Alphacorona- MATERIALS AND METHODS: The keywords virus, Deltacoronavirus, Gammacoronavirus, and of “remdesivir”, “COVID-19” and “SARS-CoV-2” 7 were systematically searched in PubMed and Betacoronavirus . The CoV is the largest known Web of Science. After removing the repetitions, RNA viruses that may be due to the particularity we summarize articles, letters, and comments of replication-transcription complex (RTC), which on remdesivir in the treatment of COVID-19. contains a few RNA processing enzymes, for ex- RESULTS: In this review, we summarize clini- ample, the 3’-5’ exoribonuclease of nonstructural cal case of using remdesivir in the treatment of proteins 148. Single strand sense RNA (+ ssRNA) COVID-19, analyzed the final treatment results, constitutes the genome of CoV, and it directly trans- and judged whether the drug was effective for the treatment of COVID-19. Also, attention was lates polyprotein 1a/1ab (pp1a/pp1ab) to encode paid to the side effects of the drug. NSPs, which composes the RTC into double-mem- CONCLUSIONS: According to the clinical re- brane vesicles (DMVs)9. Afterward, RTC synthe- sults, it was found that remdesivir was effec- sizes a nested set of subgenomic RNAs (sgRNAs) tive in the treatment of COVID-19. The drug has by a manner of discontinuous transcription10. The side effects, but the symptoms were mild and genes located downstream of ORF1b are activated disappeared immediately after discontinuation of medication. by these subgenomic messenger RNAs (mRNAs) and begin to encoding accessory and structural Key Words: proteins11. Sequence analysis and phylogenic trees COVID-19, Remdesivir, Antiviral. demonstrate that the SARS-CoV-2 belongs to the genus Betacoronavirus and possesses a typical ge- nome structure of CoV. Introduction The outbreak of COVID-19 has been defined as an epidemic, but there are still no monoclonal Since December 2019, ever-increasing pneu- antibodies, drugs or vaccines which have been monia patients have been discovered in Wuhan, approved to treat human infections caused by China1-3. disease 2019 (COVID-19) . Currently, remdesivir (GS-5734) was identified by WHO as the name of this pneu- is the most bright antiviral for combating SARS- monia. Studies4,5 have shown that COVID-19 is CoV-212. Remdesivir is a mono Phosphoramidate caused by a new virus of Severe Acute Respira- of an analog that can effec- tory Syndrome Coronavirus 2 (SARS-CoV-2). tively inhibit an array of RNA virus families. The According to the gene sequence, SARS-CoV-2 mechanism of remdesivir against the respiratory is relevant with two bat-derived SARS-like coro- syncytial virus, virus, and Nipah virus is naviruses (with 88% identity) and has rapidly through delaying chain termination of nascent vi- spread throughout the world6. The outbreak has ral RNA13. Remdesivir is a drug not only with po- propagated to more than 160 countries with more tent antiviral activity in vitro but also have ther- than 18,206, 000 confirmed cases, and more than apeutic efficacy in vivo. Remdesivir is a potential 692,000 confirmed deaths on worldwide until broad-spectrum antiviral drug, the antiviral effect Aug 4th 2020 (https://ncov.dxy.cn/ncovh5/view/ of MERS-CoV, bat CoV MERS-CoV and SARS- ?scene=2&clicktime=). CoV strains was also verified14,15. Here we review

Corresponding Author: Xianfeng Ding, MD; e-mail: [email protected] 541 Y.-N. Hong, J. Xu, G.B.K. Sasa, K.-X. Zhou, X.-F. Ding the literature on valid but not recognized antiviral IL-6 antagonists drug remdesivir. Subsequently, we analyzed the With the deepening of disease analysis, more feasibility of treatment of COVID-19 from the clinical data suggest that cytokine release syn- successful cases and pharmacological character- drome (CRS) plays a vital role in the pathological istics of remdesivir. process of COVID-19. Chemokines and inflam- matory cytokines, including monocyte chemoat- tractant protein-1 (MCP-1), interleukin-6 (IL-6), Emerging Therapeutic Strategies interleukin-1β (IL-1β) and protein 10 (IP10) are for COVID-19 patients significantly raised in COVID-19 patients. This phenomenon is more common in some severe pa- At present, healthcare systems all over the tients22,23. world are under unprecedented pressure from the COVID-19 epidemic caused by SARS-CoV-2. Chloroquine Though the number of infected individuals increas- As a widely used antimalarial drug, Chloro- es, there are no officially recognized effective thera- quine is possible benefit in the intervention of peutic agents or vaccines to treat the virus, because patients attacked by the SARS-CoV-224. Chloro- of the continuous development of clinical data and quine is considered to be safe and reliable, and evolving research respecting the virology of SARS- side effects are temporary and generally moder- CoV-2. There have a potential list of repurposed ate. Nevertheless, the margin between the tox- medicine with appropriate therapeutic efficacies ic dose and the therapeutic dose of chloroquine and pharmacological effects in curing COVID-19 is very narrow. Chloroquine poisoning may be patients. These therapeutic agents and drugs include life-threatening25. supporting agents (Azithromycin, Corticosteroids, and IL-6 antagonists) and antiviral agents (chloro- quine, hydroxychloroquine, and remdesivir), among Hydroxychloroquine has been considered to be others with therapeutic efficacies and pharmacolog- a potential drug in treating COVID-19 patients. It ical for curing COVID-19 patients. has been reported that hydroxychloroquine can cause dangerous side effects when the dosage is Azithromycin not accurately controlled26. Azithromycin is a kind of semi-synthetic mac- rolide antibiotics used to treat infections like si- Remdesivir nusitis, pharyngitis, and bronchitis, pneumonia, Remdesivir is used to cure MERS-CoV, Eb- tonsillitis, and other respiratory tract infections16. ola, and SARS-CoV as an adenosine nucleotide Numerous researches have reported that azith- analog. It is a promising broad-spectrum antiviral romycin showed resistance to viral pathogens in drug. It leads to premature termination of chain vitro17-19. Clinically, azithromycin usually com- extension by entering the new viral RNA13. Clin- bining with other drugs to treat a viral infection. ical trials have been carried out to treat Ebola vi- rus27. Currently, it is in clinical trials stage to treat Corticosteroids the SARS-CoV-2 virus. Corticosteroids are usually prescribed for vari- ous symptoms because they have a broad range of effects on the human body. Corticosteroids demon- Mechanism of Inhibition strate many therapeutic uses that are well-known. of RNA Polymerase by Remdesivir They also have many duration-dependent and dose toxicities20. In theory, corticosteroids may reduce The genomic RNA replication of SARS-CoV-2 the risk of ARDS and regulate the inflammatory depends on a multi-subunit replication-and-tran- response in patients with COVID-19. In the past, scription complex of viral Nsps28. The catalytic systemic corticosteroids have been widely used to subunit Nsp12 is a critical component of this com- treat coronavirus infections [Middle East respira- plex, which is located in RNA dependent RNA tory syndrome (MERS) and SARS]; however, after polymerase (RdRp)29. Nsp12 is responsible for the summarizing the clinical results of the use of corti- formation of the RdRp domain, Nsp13 codes for costeroids in SARS and the published literature, it RNA helicase domain, and RNA 5’-triphospha- is found that the serious side effects of corticoste- tase, Nsp14 encodes exoribonuclease (ExoN) that roids should not be ignored21. can help the replication conformity. Finally, Nsp16

542 Remdesivir as a broad-spectrum antiviral drug against COVID-19 activates 2’- O-methyltransferase activity30. These mismatch and/or substitution of natural nucleo- pieces of evidence prove that if the virus needs to tides by binding to extended nucleotide chains, survive in the host, it needs to promote essential leading to mutations that may impair RNA syn- synthesis, translation, and replication through thesis, structure, or protein function or RNA NSP protein. To effectively suppress viral RNA protein interaction34. Through these processes, replication, nucleoside analogs must outcompete the genome of the virus is transformed by NIS, exonuclease activity or avoid the detection of the and this mutation causes a gradual decrease in exonuclease. Remdesivir’s proofreading ability the fitness of the virus in each successive repli- has been proven better than Nsp12, and the viru- cation cycle. Finally, NIs may cause exhaustion lence of a drug-resistant virus will be reduced14,31. in the pools of natural nucleotides35. Remdesivir The current hypothesis is that RdRp is the target acts as a delayed RNA chain terminator resist of remdesivir13,32. the virus. The corresponding triphosphate is the Remdesivir is a chemically synthesized ana- active form of remdesivir. Remdesivir-TP com- log of purines and pyrimidines, with a molecu- petes with ATP in the process of viral genomes lar mass of 602.6, and the molecular formula is replication, causing chain termination and dis- 36 C27H35N6O8P. It is used as a nucleotide and nucle- rupt subsequent replication or transcription . oside analogue inhibitor (NIS) in the treatment The inhibition process occurred in the early of viral infection33. NIS inhibits virus replica- stage of virus infection14. Efforts to study the tion through a variety of mechanisms (Figure mechanism of remdesivir inhibiting coronavirus 1). First, exogenous nucleotides can bind to the replication not only provide the theoretical and replicating viral genomes that may lead to chain clinical experimental basis for the treatment of termination, thus interrupting subsequent repli- COVID-19 but also provide broad-spectrum an- cation or transcription. Secondly, NIs may cause tiviral drugs for future CoV outbreaks.

Figure 1. Mechanisms of inhibition by nucleoside and nucleotide analogues. Schematic diagram shows the normal process of virus replication, and 1) the decrease of replication fidelity caused by the incorporation of mutagens, 2) the depletion of naturally produced nucleotide library, and the premature termination of the chain caused by specific chain terminator.

543 Y.-N. Hong, J. Xu, G.B.K. Sasa, K.-X. Zhou, X.-F. Ding

The Clinical Efficacy of Remdesivir patients receiving remdesivir, as compared with in COVID-19 Pneumonia 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 A quarantine facility in Southern California to 1.55; p<0.001). The Kaplan- Meier estimates of reported the case of a 51-year-old Chinese woman mortality by 14 days were 7.1% with remdesivir from Wuhan who was diagnosed with COVID-19. and 11.9% with placebo (hazard ratio for death, She had typical COVID-19 clinical features, 0.70; 95% CI, 0.47 to 1.04)39. It can be proved that whose NP (nasopharyngeal swab) and OP (oro- remdesivir is significantly effective in the treat- pharyngeal swabs) are positive. During the first ment of patients with COVID-19. 6 days, the treatment given to the patient was However, not all cases have satisfactory re- supportive, including antipyretic therapy and in- sults. For example, a 77-year-old female with a travenous hydration. Through 6 days of support- history of hyperlipidemia and hypertension ac- ive treatment, patient was initiated to remdesivir companied by fever, cough, and exacerbation due to worsened condition (mild abnormal liver of respiratory distress was actively treated with function and changing chest X-ray results). This high doses of the anti-IL-6 , patient got cured and came out after 2 weeks of ascorbic acid, and hydroxychloroquine, during hospitalization. In this case, it can be found that intensive care unit treatment. Subsequently, she the clinical conditions of the patient improved received a loading dose of remdesivir, but did not after the initiation of remdesivir. There is no re- complete the course of treatment due to organ ported any significant side effects of the use of failure, and vasopressin was required to maintain remdesivir37. organ failure and hemodynamic stability. After a In another case, the patient was diagnosed series of treatment, she was still in critical condi- with severe pneumonia and SARS-CoV-2 RNA tion and she passed away peacefully in the light of was found in his BALF. In the initial treat- the family’s wishes40. Besides, of the five patients ment, azithromycin, hydroxychloroquine and reported at the University of Bichat Hospital, four broad-spectrum antibiotics were used to combat patients had side effects while using remdesivir the SARS-CoV-2 virus and bacterial infections. and thus interrupted the treatment. Finally, two After treatment with these medicine, his clinical patients died, and three patients were discharged. disorder include fever, fatigue, cough, and dys- Two of the four patients who had side effects were pnea did not improve. Subsequently, Anti-IL-6 under 40 years old. They did not have organ fail- intervention therapy decreased the level of IL-6 ure and were all discharged from the hospital af- gradually, but the condition was still deteriorat- ter discontinuing remdesivir. The other two had ing. To alleviate the disease, patient is initiated organ failure and eventually died41. Due to the in- on compassionate use remdesivir along with hy- adequate sample of these deaths, we cannot con- droxychloroquine and steroids and maintained clude that the side effects of remdesivir treatment support measures. Within 24 hours after medica- are fatal and are not suitable for the treatment of tion, the patient’s clinical conditions improved38. COVID-19. In addition to the specific diseases mentioned More cases about remdesivir in the treatment of above, there are also large-scale experiments COVID-19 are summarized in Table I. According being carried out. They designed a randomized, to these results, it can be proved that the effect of double-blind, placebo-controlled trial in which remdesivir in the treatment of COVID-19 is signif- patients are randomly assigned to receive either icant. Even if there are individual cases of adverse remdesivir or placebo for ten days and to re- reactions reported, it cannot be proved that the fa- ceive intravenous remdesivir in adult patients tal adverse reactions are caused by remdesivir. with COVID-19. Finally, the effect of the drug is judged according to the recovery time, discharge, or hospitalization for infection control only. In Conclusions this study, 538 patients are randomly assigned to the drug group, and 462 patients complete the Based on the review and the available evi- study, excluding patients who stop treatment be- dence, it seems that remdesivir has a potential role cause of adverse events or serious adverse events in the treatment of COVID-19 clinical syndrome. other than death or because of patients’ with- Although there are a lot of clinical data to prove drawal of consent. The median recovery time is the benefits of remdesivir, a higher level of data 11 days [95% confidence interval [CI], 9-12] in support is still needed.

544 Table I. Summary of clinical cases.

No. of Symptom Initiation of Duration Dose Outcome Antibiotic patients remdesivir (Day) (from onset)

1 Fevers, chills, sweats, nonproductive cough 6 19 200 mg intravenous on day 1 Discharged No37 followed by 100 mg daily 1 Ongoing fever, chills, cough, fatigue, ≥20 9 200 mg intravenous on day 1 Discharged Yes38 and shortness of breath followed by 100 mg daily 1 Bilateral opacities on chest X-ray and 10 4 200 mg intravenous on day 1 Death Yes40 had continued intermittent fevers with followed by 100 mg daily generalized weakness, cough, lethargy, and dyspnea 4 Severe pneumonia, RT-PCR positive Unknown 10 200 mg intravenous on day 1 Symptoms improved Yes42 for SARS-CoV-2 followed by 100 mg daily in three patients 5 Fever, diarrhea and cough 6-11 2-14 200 mg intravenous on day 1 Two people died and the Unknown41 followed by 100 mg daily others were re-covered 53 Confirmed SARS-CoV-2 infection, oxygen 1-8 10 200 mg intravenous on day 1 Symptoms improved or No43 saturation of 94% or less while the patient followed by 100 mg daily discharged in 46 patients 158 RT-PCR positive for SARS-CoV-2 ≤10 10 200 mg intravenous on day 1 Symptoms improved No44 followed by 100 mg daily 397 Confirmed SARS-CoV-2 infection, oxygen 4 5-10 200 mg intravenous on day 1 Symptoms improved in No45 saturation of 94% or less while they were followed by 100 mg daily 354 patients breathing ambient air, and radiologic evidence of pneumonia 462 Confirmed by the hospital without detailed 6-12 9-12 200 mg intravenous on day 1 168 recovered (this No explanation going on followed by 100 mg daily experiment is still descrip -tion39

545 Y.-N. Hong, J. Xu, G.B.K. Sasa, K.-X. Zhou, X.-F. Ding

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