key: cord-0916652-ilovsn4w
authors: Chiu, Yu-Jen; Chiang, Jo-Hua; Fu, Chih-Wei; Hour, Mann-Jen; Ha, Hai-Anh; Kuo, Sheng-Chu; Lin, Jen-Jyh; Cheng, Ching-Chang; Tsai, Shih-Chang; Lo, Yu-Shiang; Juan, Yu-Ning; Cheng, Yih-Dih; Yang, Jai-Sing; Tsai, Fuu-Jen
title: Analysis of COVID-19 prevention and treatment in Taiwan
date: 2021-03-01
journal: Biomedicine (Taipei)
DOI: 10.37796/2211-8039.1185
sha: cfe5af4858f1e2f95d49cf1ac40054dc8609eb49
doc_id: 916652
cord_uid: ilovsn4w

Coronavirus disease 2019 (COVID-19) has been spreading worldwide with a mind-boggling speed. According to a statement from World Health Organization (WHO), COVID-19 has infected more than six billions people and caused more than one and half million passing in the world. Based on previous experience with SARS, the Taiwanese government had decided to block viral transmission during its early stages. This review sums up the clinical characteristics, Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) viral infection process, diagnostic methods, preventive strategy, and the executive proportions of COVID-19, as well as the name-based mask distribution system (NBMDS) in Taiwan. We also give a review of the conceivable sub-atomic pharmacologic systems against SARS-CoV-2 specialists and the blend of remdesivir (GS-5734), chloroquine (CQ), and hydroxychloroquine (HCQ). Lastly, we summarized the therapeutic agents against COVID-19 as mentioned by COVID-19 treatment guidelines. In this review, development of novel anti-SARS-CoV-2 viral agents, vaccines for COVID-19 therapy or an effective combination therapy can be expected based on all the information accumulated. Last but not least, we might want to stretch out our best respects to all medical providers in their worldwide battle against COVID-19.

C oronavirus disease 2019 (COVID- 19) , brought about by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has spread worldwide with a mind-boggling speed. According to a statement from World Health Organization (WHO), COVID-19 has infected more than six billions people and caused more than one and half million passing in the world [1e6] . Based on previous experience with severe acute respiratory syndrome (SARS), the Taiwanese government had decided to block viral transmission during its early stages. Presently, early blockage of SARS-CoV-2 transmission has been the key point in protecting against COVID-19 [7, 8] . Confirmed cases in Taiwan have been lower than those in other countries. Accordingly, the Taiwan Center for Disease Control (TCDC) had revealed 675 affirmed cases and seven passing till the end of November 2020 (Fig. 1A) . The majority of the confirmed cases were indigenous and imported, with a peak age of 20-29 years (Fig. 1B) .

Taiwan is only 81 miles away from the coast of China, has been constantly alert and ready to act on potential epidemics arising from China considering the insufferable experiences gained from the severe acute respiratory syndrome (SARS) epidemic of 2003 [8] . Given that most patients shared nonspecific clinical and laboratory findings, comprehensive surveillance of detailed exposure history for suspected patients, and application of rapid detection tools are required. Through the combination of border control, rapid testing and quarantine of individuals with contact history, isolation, real-time linking of informative records with the healthcare system, and protection of health care worker safety through Traffic Control Bundling, Taiwan had been able to effectively control the COVID-19 epidemic [9, 10] .

We sums up the clinical characteristics, SARS-CoV-2 viral life cycle and infection process, diagnostic methods, preventive strategy, and the executive proportions of COVID-19, as well as the namebased mask distribution system (NBMDS) in Taiwan. We also give a review of the conceivable sub-atomic pharmacologic systems against SARS-CoV-2 specialists. Lastly, we summarized the therapeutic agents against COVID-19 as mentioned by COVID-19 treatment guidelines.

As indicated by literature reviews, fever, weariness, headache, dry cough, sputum production, haemoptysis, sore throat, and diarrhoea have been the most usual manifestations at the beginning of COVID-19 infection, with other symptoms including muscle ache, dyspnoea, productive cough, haemoptysis, and stroke [11] . The time period of symptoms onset is around 5.2 days after infection [11] . It was reported that up to 75% of patients with COVID-19 infection stay asymptomatic [11, 12] . Around 14% of patients develop severe symptoms and signs, including pneumonia and adult respiratory distress syndrome (ARDS), requiring hospitalization and oxygen treatment, and about 5% of patients need intensive care and support. From admission to intensive care unit, the time period of length was around 10 days, while the span between manifestation beginning and passing went from roughly 2 weeks to 2 months [11, 13, 14] . Fig. 2 revealed the symptoms of signs as COVID-19 infection progressing.

Finding of laboratory tests incorporate raised lactate dehydrogenase and ferritin levels. Leucopoenia and lymphopenia have been most ordinarily noticed discoveries, while white blood cell (WBC) counts can vary [15e17]. Findings of chest radiography and computed tomography (CT) are assorted and vague, regularly introducing as local patchy shadowing, bilateral patchy shadowing or multiple ground-glass opacity lesions. As the infection advances, ground-glass opacity lesions might advance into consolidation or crazy-paving pattern finding (interlobular/intralobular septal thickening) [18e20].

Diagnosis tests of COVID-19 in Taiwan were summarized in Table 1 . There are three methods which have been popularly applied for the diagnosis of SARS-CoV-2, including:

(1) A nucleic acid amplification test (NAAT) by realtime reverse transcription polymerase chain reaction (rRT-PCR).

(2) Antigen test screening.

(3) Serologic and/or antibody testing.

A nucleic acid amplification test (NAAT) by realtime reverse transcriptase polymerase chain reaction (rRT-PCR) is the gold standard for detecting SARS-CoV-2 infection. The specificity and sensitivity are very high. However, this method has a window period of up to 5 days after virus exposure. Antigen tests can rapidly identify people with SARS-CoV-2 infection with low cost, which is critical for preventing transmission. However, low accuracy is the major problem of antigen test. A nucleic acid amplification test (NAAT) should be considered, if a person who is highly suspected of SARS-CoV-2 infection with negative results of initial antigen tests. Serologic and/or antibody testing is not suit for diagnosing initial SARS-CoV-2 infection, because these antibodies to SARS-CoV-2 were merged after 21 days or more after infection. But, the test can investigate people with prior or recent SARS-CoV-2 infection (Fig. 3) [21e24].

Both SARS-CoV-2 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) have been considered profoundly pathogenic. As shown in Fig. 4A , the schematic structure of SARS-CoV-2 included spike proteins (S), lipid membrane, membrane proteins (M), envelope proteins (E), and nucleocapsid protein enclosing ssRNA (N). Single stranded RNA genome of SARS-CoV-2 was shown in Fig. 4B [25] . The SARS-CoV-2 use their spike proteins to bind host cell membrane receptors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), for passage. Fig. 5 shows that there are eight significant stages of the life cycle of SARS-CoV-2. Stage 1 is that SARS-CoV-2 enters the target cell through endocytosis or fusion after authoritative to ACE2 receptor and TMPRSS2. The SARS-CoV-2 envelope advances viral RNA genome discharge into the host cell cytoplasm through fusing with the endosome layer in the lysosomal corrosive condition. Subsequently, stage 2 is genome RNA release. The coronavirus main proteinase (3CLpro) is deciphered for the replication of genomic RNA. From that point, replicase polypeptide is proteolysis, delivering helicase and RNA-dependent RNA polymerase (RdRp) (stage 3 and 4). In stage 5, SARS-CoV-2 at that point goes through viral RNA replication in the host cells. In stage 6, the viral sub-genome is deciphered. Spike proteins (S), lipid membrane, membrane proteins (M), envelope proteins (E), and nucleocapsid protein enclosing ssRNA (N) are packaging through Golgi apparatus and the endoplasmic reticulum (stage 7). In stage 8, a novel virion is packed and shaped by N protein and other auxiliary proteins communicate with viral genomic RNA. Finally, the amassed virion is then delivered by means of exocytosis into the extracellular compartment [11, 26, 27] .

SARS-CoV-2 infection possesses nonspecific clinical manifestation, so that it can be easily transmitted from mild symptomatic or asymptomatic individuals to others. As of now, avoidance of viral passage into the human body seems to be the most ideal choice for controlling viral spread. The Taiwan Center for Disease Control (TCDC) has set up specialized rules for COVID-19. Coming up next are vital points for forestalling viral spread: (1) Avoiding travelling to affected countries.

(2) Regular decontamination with 5% to 10% sodium hypochlorite. (3) Social distance, including at least 1.5 m indoors and at least 1 m outdoors. (4) Keeping proper hygiene of individuals, such as frequent hand washing with soap or alcoholbased hand sanitisers. (5) Personal protective equipment, such as gloves, eye protection, gowns and medical masks [28] .

Because of the supply shortages of face masks, The Taiwanese government has developed guidelines to protect the health and safety of the public from the global novel coronavirus outbreak. Fig. 6 details the processing of the name-based mask distribution system (NBMDS) in Taiwan [29] . While medical and surgical masks should be prioritised for health care workers, the general public can wear cloth face masks made from household items, such as two layers of cotton fabric, T-shirts or bedsheets. Medical masks can filter 5-mm particles from the air reaching the mouth/nose, reducing the transmission of respiratory droplets to others and prevent blood or other potentially infectious materials from reaching the wearer's skin, mouth or mucous membranes. Fig. 7 summarise the medical mask materials and associated principles [29e34]. In addition, the structure and composition of the different virus families occur affect their reaction to disinfectants. Components, such as 75% ethanol [35e38], sodium hypochlorite (1000 ppm (0.1%)-10,000 ppm (1%)) [33, 38, 39] , hypochlorous acid (10 ppm-30 ppm) [33,38e40] , chlorine dioxide [40] , soap [41] and hydrogen peroxide (0.5%) [42e44] and others [44e47] have been used to kill bacteria and viruses. Table 2 lists the chemical formula and preparation concentration of the disinfectants, as well as associated principles.

Currently, there is still lacking strong clinical evidence of existing anti-viral agents and vaccine against SARS-CoV-2 infection. Supportive treatment is crucial, including oxygen therapy for hypoxemia and respiratory distress, intravenous fluids Table 3 [48, 49] . Currently, three clinical trials on COVID-19 are ongoing in Taiwan (NCT 04292899, NCT 04292730 and NCT 03808922), with remdesivir (Veklury®) as the primary anti-SARS-CoV-2 agent.

In the one-year period since the epidemic arose, scientists around the world made many efforts to find ways to prevent and treat the disease [11] .

Based on the accumulating data, guidelines on COVID-19 treatment is gradually being updated and modified by the World Health Organization (WHO), United States National Institutes of Health (NIH) as well as other Health authorities [1e5]. Categorically, agents used for COVID-19 can be roughly divided into 3 main groups (Fig. 8) :

(A) Anti-viral therapy agents. (B) Immune-based therapy agents. (C) Adjunctive therapy agents. In the latest update of NIH's guideline (updated on Nov 18th, 2020), bamlanivimab (LY-CoV555) is the new therapy to fight against COVID-19. This synthetic antibody-based treatment is received Emergency Use Authorization, but NIH recommended that is not a standard care for COVID-19 [2] . It can be used for non-hospitalized patients with mild to moderate COVID-19 and having high risk of progressing to severe condition. Earlier, remdesivir received approval from Europe Commission and US-FDA, become the first official drug to treat COVID-19 [1, 2] . Lopinavir/ritonavir (LPV/r; Kale-tra®) and ivermectin (Stromectol®) were proposed as potential therapeutic for COVID-19 in early 2020 [50] . However, the limited clinical improvement, no significant in lowering morality rate, and made these therapeutics got recommendation against by the guidelines, except for clinical trials. Other treatments of anti-viral therapies can be found at China's guideline (the latest updated on Aug 18th, 2020) with the recommendation of using chloroquine sulfate (CQ) and ribavirin (Robatrol®) combined with interferon a or lopinavir/ritonavir (LPV/ r; Kaletra®) [4, 51] . Also, in this guideline, the uses of traditional medicine were recommended for treatment of COVID-19. The distinctive, different opinions of China's guideline compared to others, and the accomplishments in controlling disease of China are worth to be analyzed (Table 4 ). However, comprehensive clinical data on that the achievements were not published so far.

Immune-based therapies for COVID-19 are considered as systemic treatments, using human blood-derived products and/or immune-modulatory therapies. As of blood-derived products, those who have recovered from SARS-CoV-2 infection can donate their convalescent plasma or immunoglobulin to make products for treatment in other patients [52, 53] . Experimental data suggested that, these products induce direct inhibitory effect against SARS-CoV-2 [53] . There is not enough evidence in clinical data for blood-derived products to be recommended by the guidelines as a standard care treatment for COVID-19 [2, 3, 5] . Other therapies, such as mesenchymal stem cells, non-SARS-CoV-2-specific intravenous immunoglobulins (IVIG) are recommended against by experts to use for COVID-19, except in clinical trial [2] . As of the corticosteroids, the most recommended agent in guidelines is dexamethasone, based on the accumulated data that showed the improvement in clinical treatment for COVID-19 patients. However, the guidelines recommended against the long-term use of dexamethasone and other corticosteroids, due to the side effects [1e5]. In addition, the combination of dexamethasone and remdesivir is suggested by the NIH's guideline [2] . Other immunmodulators (IL-1 inhibitors; anti-IL-6 receptor monoclonal antibody; Interferons a/b; Bruton's tyrosine kinase inhibitors and Janus kinase inhibitors) are mentioned cautiously by the guidelines. Due to the lack of supportive evidence, these products are not recommended for use in patients with COVID-19, except in well-designed trials [2, 3, 5] .

Adjunctive therapy agents for use in COVID-19 course are recommended by the guidelines, including:

(1) Anti-thrombotic therapies.

(2) Vitamin C and vitamin D.

(3) Zinc supplementation.

Because the symptoms of COVID-19 are associated with inflammation and a pro-thrombotic state, anti-thrombotic agents and anti-platelet agents were suggested as useful adjunct to COVID-19 treatment [2, 5] . Recommendations for anti-thrombotic agents were given by the guidelines, such as apixaban (Eliquis®), rivaroxaban (Xarelto®), edoxaban (Lixiana®) and dabigatran (Pradaxa®) (by the NIH -USA) and acetylsalicylic acid (Aspirin®) (by NCCET-Australia and NHC-China). However, additional measures should be taken to prevent the possible unwanted effect for certain patient groups and risk/benefit should be considered [5] . Additionally, the uses vitamin and mineral supplements were suggested as a preventive measure for COVID-19, as well as for attenuating the complications during course of the infection. The products of vitamin C, vitamin D and zinc supplementations were suggested by several studies. However, the rationale use, benefits and harms in particular group of patients were needed further study to be clarified [1, 2, 5] .

Please refer to the previously published article "Approaches towards fighting the COVID-19 pandemic (Review)" for molecular pharmacological mechanisms in detail [11] .

Remdesivir (Compound 12) was synthesised by Siegel et al. as illustrated in Schem 1 (Fig. 9 ) [54] . The iodo-based compound 1 was reacted with Turbo Grignard reagents via metalehalogen exchange, followed by the addition of ribolactone 2 to afford the glycosylation product 3. Treatment of 3 with TMSCN, TMSOTf and TfOH at À78 C afforded 4, which yielded benzyl deprotection product 5 after reacting with BCl 3 . Acetonide protection of the 2 0 ,3 0 -hydroxyl moieties with 2,2-dimethoxypropane in the presence of H 2 SO 4 afforded 6. 2-Ethyl-1butanol 7 and L-alanine 8 were treated with HCl (g) to generate ester product 9, which was reacted with OP(OPh)Cl 2 under base conditions, followed by 4nitrophenol to obtain the p-nitrophenolate 2-ethylbutyl-L-alaninate prodrug precursor 10. The coupling reaction between 6 and 10 under MgCl 2 generated 11, after which in situ acetonide deprotection was performed through concentrated HCl to afford target molecule remdesivir (Compound 12). Molecular docking of remdesivir binding to the RNA-dependent RNA polymerase (RdRp) was shown on Supplementary video S1 (https://youtu. be/s_SUUMO7URw). As shown in Fig. 10 , chloroquine (Compound 25) was synthesised by Drake N. L. et al. and Price Ch. C. et al. as described in Schem 2 [55, 56] . Accordingly, 4,7-Dichloroquinoline 19 was prepared from 3-chloroaniline 13 via 1,4-addition with ethoxymethylenmalonic acid 14, thermal heterocyclisation, hydrolysis, decarboxylation and POCl 3 chlorination. Novaldiamine 24 was synthesised following three steps. Acetoacetic ester 20 alkylation with 2-diethylaminoethylchloride 21 generated 2diethylaminoethylacetoacetic acid ester 22, which yielded 1-diethylamino-4-pentanone 23 upon acidic hydrolysis using hydrochloric acid and simultaneous decarboxylation. Reductive amination of this 

This review describes several clinical manifestations of COVID-19, analyses the SARS-CoV-2 genome and outlines the life cycle of SARS-CoV-2. Several methods have been used to examine SARS-CoV-2 infections. The Taiwanese government has established several policies for controlling viral spread. Last but not least, we summarized the therapeutic agents against COVID-19 as mentioned by COVID-19 treatment guidelines.

To avoid direct contact with suspected COVID-19 cases, viral secretions and infected droplets, the following relevant preventive measures should be followed:

(1) Pay attention to and cooperate with the latest epidemic prevention policies issued by the government. (2) Maintain hand hygiene habits, particularly avoiding touching the eyes, nose and mouth with unclean hands. We expect Taiwan to globally interact and cooperate with other countries to develop rapid and accurate screening assays, produce vaccines, design novel agents against SARS-CoV-2 and reduce the side effects. Ultimately, our long-term goal is to be free from COVID-19.

Substrates:

1. formamide e available at Sigma-Aldrich 2. 2-brom-4-chlor-acetophenon e available at Sigma-Aldrich Products:

1. 7-chloro-quinolin-4-ol e available at Sigma-Aldrich 1. n4,n4-diaethyl-1-methyl-butandiyldiamin e available at Sigma-Aldrich 2. 7-chloro-quinolin-4-ol e available at Sigma-Aldrich

Products:

1. (-)-chloroquine e available at Sigma-Aldrich 

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We gratefully acknowledge the support of NVI-DIA AI Tech Center for having Clara Discovery and GPU to generate molecular dynamic video on performing the molecular docking to RdRp to our research. We wish to acknowledge the work of Nian-Gu Chen, Pei-Jen Chung for their assistance on this work. We also thank Merck Ltd. Taiwan Company for providing Synthia Organic Retrosynthesis Software (Synthia™).

YJC, JHC, FJT and JSY were involved in the conception of this study. CWF, MJH, HAH, SCK, JJL, YNJ, YDC and CCC were involved in the literature search and critical reviewing of the manuscript. SCT, JSL, SCK, FJT and JSY were involved in the preparation of the draft of the manuscript. YJC, JHC, FJT and JSY were involved in the revising and editing of the manuscript. All authors have read and approved the final manuscript. Products: 

Substrates:

Products:1. 7-amino-quinolin-4-ol e available at Sigma-Aldrich

Substrates:

Products: