key: cord-1011531-2tu707ng
authors: Zhang, Lei; Liu, Yunhui
title: Potential interventions for novel coronavirus in China: A systematic review
date: 2020-03-03
journal: J Med Virol
DOI: 10.1002/jmv.25707
sha: 6f6869455fc1633063437bef6bd5400ed0b0be23
doc_id: 1011531
cord_uid: 2tu707ng

An outbreak of a novel coronavirus (COVID‐19 or 2019‐CoV) infection has posed significant threats to international health and the economy. In the absence of treatment for this virus, there is an urgent need to find alternative methods to control the spread of disease. Here, we have conducted an online search for all treatment options related to coronavirus infections as well as some RNA‐virus infection and we have found that general treatments, coronavirus‐specific treatments, and antiviral treatments should be useful in fighting COVID‐19. We suggest that the nutritional status of each infected patient should be evaluated before the administration of general treatments and the current children's RNA‐virus vaccines including influenza vaccine should be immunized for uninfected people and health care workers. In addition, convalescent plasma should be given to COVID‐19 patients if it is available. In conclusion, we suggest that all the potential interventions be implemented to control the emerging COVID‐19 if the infection is uncontrollable.

Coronaviruses (CoVs) belong to the subfamily Orthocoronavirinae in the family of Coronaviridae in the order Nidovirales, and this subfamily including α-coronavirus, β-coronavirus, γ-coronavirus, and deltacoronavirus. 1 Coronaviruses primarily cause enzootic infections in birds and mammals and, in the last decades, have shown to be capable of infecting humans as well. 2 The outbreak of severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012 has demonstrated the lethality of coronaviruses when they cross the species barrier and infect humans. 2 

belong to the β-coronavirus family. 3 Recently, a novel flu-like coronavirus related to the MERS and SARS coronaviruses was found at the end of 2019 in China 4,5 and the evidence of human-to-human transmission was confirmed among close contacts. 6 The genome of COVID-19 is a single-stranded positive-sense RNA. 7 The sequence analysis showed that the COVID-19 possessed a typical genome structure of coronavirus and belonged to the cluster of β-coronaviruses including SARS-CoV and MERS-CoV. 7 COVID-19 was more than 82% identical to those of SARS-CoV. 8 

Vitamin A is the first fat-soluble vitamin to be recognized and β-carotene is its plant-derived precursor (Table 1 ). There are three active forms of vitamin A in the body, retinol, retinal, and retinoic acid.

Vitamin A is also called "anti-infective" vitamin and many of the body's defenses against infection depend on an adequate supply. Researchers have believed that an impaired immune response is due to the deficiency of a particular nutritional element. 10 Vitamin A deficiency is strongly involved in measles and diarrhea 11 and measles can become severe in vitamin A-deficient children. In addition, Semba et al 12 had reported that vitamin A supplementation reduced morbidity and mortality in different infectious diseases, such as measles, diarrheal disease, measles-related pneumonia, human immunodeficiency virus (HIV) infection, and malaria. Vitamin A supplementation also offers some protection against the complications of other life-threatening infections, including malaria, lung diseases, and HIV. 13 Jee et al 14 had reported that low vitamin A diets might compromise the effectiveness of inactivated bovine coronavirus vaccines and render calves more susceptible to infectious disease. The effect of infection with infectious bronchitis virus (IBV), a kind of coronaviruses, was more pronounced in chickens fed a diet marginally deficient in vitamin A than in those fed a diet adequate in vitamin A. 15 The mechanism by which vitamin A and retinoids inhibit measles replication is upregulating elements of the innate immune response in uninfected bystander cells, making them refractory to productive infection during subsequent rounds of viral replication. 16 Therefore, vitamin A could be a promising option for the treatment of this novel coronavirus and the prevention of lung infection.

B vitamins are water-soluble vitamins and work as part of coenzymes. Each B vitamin has its special functions. For example, vitamin B2 (riboflavin) plays a role in the energy metabolism of all cells. Vitamin B2 deficiency had been suspected to occur among US elderly. 17 Keil et al 18 had reported that vitamin B2 and UV light effectively reduced the titer of MERS-CoV in human plasma products. Vitamin B3, also called nicotinamide, could enhance the killing of Staphylococcus aureus through a myeloid-specific transcription factor and vitamin B3 was efficacious in both prophylactic and therapeutic settings. 19 Moreover, vitamin B3 treatment significantly inhibited neutrophil infiltration into the lungs with a strong anti-inflammatory effect during ventilatorinduced lung injury. However, it also paradoxically led to the development of significant hypoxemia. 20 Vitamin B6 is also needed in protein metabolism and it participates in over 100 reactions in body tissues. In addition, it also plays important role in body immune function as well. As shortage of B vitamins may weaken host immune response, they should be supplemented to the virus-infected patients to enhance their immune system. Therefore, B vitamins could be chosen as a basic option for the treatment of COVID-19.

Vitamin C is another water-soluble vitamin and it is also called ascorbic acid, which means "no-scurvy acid." Vitamin C is best known for its role in the synthesis of collagen in connective tissues and acts as an antioxidant. Vitamin C also supports immune functions and protects against infection caused by a coronavirus. 21 infection. Vitamin C may also function as a weak antihistamine agent to provide relief from flu-like symptoms such as sneezing, a running or stuffy nose, and swollen sinuses. 23 Three human controlled trials had reported that there was significantly lower incidence of pneumonia in vitamin C-supplemented groups, suggesting that vitamin C might prevent the susceptibility to lower respiratory tract infections under certain conditions. 24 The COVID-19 had been reported to cause lower respiratory tract infection, so vitamin C could be one of the effective choices for the treatment of COVID-19.

Vitamin D is not only a nutrient but also a hormone, which can be synthesized in our body with the help of sunlight. In addition to its role in maintaining bone integrity, it also stimulates the maturation of and omega-6 PUFAs predominantly promote anti-inflammatory and pro-inflammatory effects. They are precursors of resolvins/protectins and prostaglandins/leukotrienes, respectively. 31 Begin et al 32 had studied plasma lipids levels in patients with AIDS and had found that a selective and specific lack of the long-chain PUFAs of omega-3 series, which are found in high concentrations in fish oils. In addition, protectin D1, the omega-3 PUFA-derived lipid mediator, could markedly attenuate influenza virus replication via RNA export machinery. In addition, treatment of protectin D1 with peramivir could completely rescue mice from flu mortality. 33 Leu et al 34 had found that several PUFAs also had anti-hepatitis C virus (HCV) activities.

Therefore, Omega-3 including protectin D1, which served as a novel antiviral drug, could be considered for one of the potential interventions of this novel virus, COVID-19.

Selenium is an essential trace element for mammalian redox biology. 35 The nutritional status of the host plays a very important role in the defense against infectious diseases. 36 Nutritional deficiency impacts not only the immune response but also the viral pathogen itself. 10 Dietary selenium deficiency that causes oxidative stress in the host can alter a viral genome so that a normally benign or mildly pathogenic virus can become highly virulent in the deficient host under oxidative stress. 10 Deficiency in selenium also induces not only impairment of host immune system, but also rapid mutation of benign variants of RNA viruses to virulence. 37 Beck et al 38 had reported that selenium deficiency could not only increase the pathology of an influenza virus infection but also drive changes in genome of coxsackievirus, permitting an avirulent virus to acquire virulence due to genetic mutation. 39 It is because that selenium could assist a group of enzymes that, in concert with vitamin E, work to prevent the formation of free radicals and prevent oxidative damage to cells and tissues. 37 It was reported that synergistic effect of selenium with ginseng stem-leaf saponins could induce immune response to a live bivalent infectious bronchitis coronavirus vaccine in chickens. 40 Therefore, selenium supplementation could be an effective choice for the treatment of this novel virus of COVID-19.

Zinc is a dietary trace mineral and is important for the maintenance and development of immune cells of both the innate and adaptive immune system. 41 Zinc deficiency results in dysfunction of both humoral and cell-mediated immunity and increases susceptibility to infectious diseases. 42 Zinc supplement given to zinc-deficient children could reduce measles-related morbidity and mortality caused by lower respiratory tract infections. 43 Increasing the concentration of intracellular zinc with zinc-ionophores like pyrithione can efficiently impair the replication of a variety of RNA viruses. 44 In addition, the combination of zinc and pyrithione at low concentrations inhibits the replication of SARS coronavirus (SARS-CoV). 44 56 In addition, interferons have also been found to be potent inhibitors of MERS-CoV replication. 57 Moreover, the combination of interferon-α-2a with ribavirin was administered to patients with severe MERS-CoV infection and the survival of these patients was improved. 57 These findings suggest that these approved IFN's could be also used for the treatment of this novel coronavirus.

Intravenous gammaglobulin (IVIg) was first developed in the late 1970s 58 and is probably the safest immunomodulating drug available for long-term use in all ages. However, it does have adverse reactions.

During the SARS outbreak in 2003, IVIg was used extensively in

Singapore. However, one-third of critically ill patients developed venous thromboembolism including pulmonary embolism despite the use of lowmolecular weight heparin prophylactic. 59 It was due to the IVIg-induced increase of viscosity in hypercoagulable states of SARS patients. 60 

Thymosin α-1 (Ta1) is a thymic peptide hormone and it has a peculiar ability to restore the homeostasis of the immune system. 61 It is was first isolated from thymic tissue in the mid-sixties and it had gained much attention for its immunostimulatory activity. 62 It was chemically synthesized and used in diseases where the immune system was hindered or impaired. 63 Besides its role in thymocyte development, thymosin α-1 could also increase resistance to glucocorticoid-induced death of the thymocyte. 64 Thymosin α-1 could also be used as immune enhancer to SARS patients and it was effective in controlling the spread of the disease. 65, 66 Methylprednisolone was often used during the current treatment of COVID-19 and the side effect of corticoid-induced death of thymocytes should be considered. So, it is wise to use thymosin α1 before the administration of methylprednisolone.

Thymopentin (TP5, munox), a synthetic pentapeptide corresponding to the active site of thymopoietin, had been shown to restore antibody production in old mice. 67 Additionally, it could enhance the antibody response in humans when it was applied subcutaneously three times a week at doses of 50 mg. 68 Moreover, thymopentin could also be used as an adjuvant treatment for non-responders or hyporesponders to hepatitis B vaccination. 69 

Levamisole, a synthetic low-molecular-weight compound, is the first member of a new class of drugs that can increase the functions of cellular immunity in normal, healthy laboratory animals. 70 Medicine could also be considered as a choice to enhance host immunity against the infection of COVID-19.

In summary, the general treatment for viral infection including nutritional interventions and all kinds of immunoenhancers has been used to enhance host immunity against RNA viral infections. Therefore, they may also be used to fight COVID-19 infection by correcting the lymphopenia of patients.

Chymotrypsin-like (3C-like) and papain-like protease (PLP) are coronavirus encoded proteins (Table 2) . They have an essential function for coronaviral replication and also have additional function for inhibition of host innate immune responses. Targeting 3C-like protease (3 CLpro) and papain-like protease (PLpro) are more attractive for the treatment of coronavirus. 77

Cinanserin Cinanserin, an old drug, is well-known for serotonin receptor antagonist. It could inhibit the 3 chymotrypsin-like (3C-like) protease and was a promising inhibitor of replication of SARS-CoV. 78 The 3CLpro was also been found to be encoded in COVID- 19. 7 Therefore, Cinanserin may be a better choice for the treatment of COVID-19 infection. 

Papain-like protease (PLP) of human coronavirus is a novel viralencoded deubiquitinase and is an IFN antagonist for inhibition of host innate antiviral immune response.

Diarylheptanoids is a natural product and is extracted from the stem bark of Alnus japonica. It had been found to be able to inhibit papainlike protease of SARS-CoV. 77 Therefore, cinanserin together with flavonoids and other natural compounds could be chosen as alternative choices to fight COVID-19

infection through targeting coronaviral proteases.

Angiotensin-converting enzyme-2 (ACE2) is a type I integral membrane protein which functions as a carboxypeptidase and is the first human homolog of ACE. 84 ACE2 efficiently hydrolyzes the potent vasoconstrictor angiotensin II to angiotensin (1-7) and it has been implicated in hypertension, cardiac function, heart function, and diabetes. 84 In addition, ACE2 is also a functional receptor of SARS-CoV and it mediates virus entry into the cell through binding with spike (S) protein. 85 

Chloroquine is a 9-aminoquinoline known since 1934. Apart from its well-known antimalarial effects, the drug also has many interesting biochemical properties including antiviral effect. In addition, it had been used against viral infection. 90 Moreover, chloroquine was also found to be a potent inhibitor of SARS coronavirus infection through interfering with ACE2, one of cell surface binding sites for S protein of SARS-CoV. 91 

Emodin is an anthraquinone compound derived from genus Rheum and Polygonum and it is also a virucidal agent. 92 Emodin could significantly block the interaction between the S protein of SARS-CoV and ACE2. Therefore, emodin might abolish SARS-CoV infection by competing for the binding site of S protein with ACE2. 93 

Promazine, anti-psychotic drug, shares a similar structure with emodin. It has been found to exhibit a significant effect in inhibiting the replication of SARS-CoV. 94 As compared to emodin, promazine exhibited potent inhibition of the binding of S protein to ACE2. These findings suggested that emodin and promazine might be able to inhibit SARS-CoV infectivity through blocking the interaction of S protein and ACE2. 93 Therefore, the monoclonal antibody (scFv80R), chloroquine, emodin, and promazine could be used as alternative choices for the treatment of COVID-19.

Nicotianamine is an important metal ligand in plants 95 and it is found a novel angiotensin-converting enzyme-2 inhibitor in soybean. 96 So, it is another potential option to be used to reduce the infection of COVID-19.

Ribavirin, a broad-spectrum antiviral agent, is routinely used to treat hepatitis C (Table 3 ). During the outbreak of SARS, ribavirin was used extensively for most cases with or without concomitant use of steroids in Hong Kong. 97 However, there was considerable skepticism from overseas and local experts on the efficacy of ribavirin. 98 Because there was a report mentioned that ribavirin had no significant activity against SARS-CoV in vitro 52 and the use of ribavirin was found to be associated with significant toxicity, including hemolysis (in 76%) and decrease in hemoglobin (in 49%). 99 

Remdesivir (RDV), a nucleoside analog GS-5734, had been reported to inhibit human and zoonotic coronavirus in vitro and to restrain severe acute respiratory syndrome coronavirus (SARS-CoV) in vivo. 104 Recently, the antiviral activity of RDV and IFN-β was found to be superior to that of LPV/RTV-IFN-β against MERS-CoV in vitro and in vivo. 101 In addition, RDV could improve pulmonary function and reduce lung viral loads and severe lung pathology in mice, which was impossible for LPV/RTV-IFN-β. 101 Recently, a first COVID-19- 

Nelfinavir is a selective inhibitor of HIV protease, which is responsible for posttranslational processing of HIV propeptides. 106 Yamamoto et al 107 had found that nelfinavir could strongly inhibit the replication of SARS-CoV. Therefore, nelfinavir could also be an option for the treatment of COVID-19.

Arbidol (ARB) is a Russian-made small indole-derivative molecule and is licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. 108 Arbidol had been found to be able to block viral fusion against influenza A and B viruses as well as hepatitis C virus. 109 Arbidol could also inhibit hepatitis C virus by blocking hepatitis C virus entry and replication in vitro. 110 In addition, arbidol and its derivatives, arbidol mesylate, had been reported to have antiviral activity against the pathogen of SARS in the cell cultures and arbidol mesylate was nearly 5 times as effective as arbidol in reducing the reproduction of SARS virus in the cultured cells. 111 

Nitric oxide (NO) is a gas with diverse biological activities and is produced from arginine by NO synthases. NO is able to interact with superoxide, forming peroxynitrite, which, in turn, can mediate bactericidal or cytotoxic reactions. 112 In addition, NO had played an important role in regulating airway function and in treating inflammatory airway diseases. 113 Rossaint et al 114 reported that the beneficial effects of NO inhalation could be observed in most patients with severe acute respiratory distress syndrome. NO was also found to inhibit the synthesis of viral protein and RNA. 115 (Table 3 ). 117 ALA, as an antioxidant, has played a pivotal role in scavenging free radicals to protect against oxidative damage in several diseases. 118 In addition, ALA also had its capability to enhance intracellular glutathione (GSH) levels 118 and to normalize the oxidative stress induced by Dexamethasone in chicken. 119 Wu et al 120 also reported that the oxidative stress in host cells was an important factor in the infectivity of human coronavirus 229E and the glucose-6-phosphate dehydrogenase (G6PD) deficiency was another factor that enhanced human coronavirus 229E infection.

The addition of α-lipoic acid to G6PD-knockdown cells could attenuate the increased susceptibility to human coronavirus 229E

infection. 120 Interestingly, Baur et al 121 also found that α-lipoic acid was effective to inhibit the replication of HIV-1. In summary, we speculate that ALA could be also used as an optional therapy for this new virus.

Females, generally, mount more robust immune responses to viral challenges than males, which can result in more efficient virus clearance. 122 Epidemiological studies showed that males experiencing a higher rate of incidence and case fatality compared with females after SARS-CoV infection. 123, 124 During the MERS outbreak, the disease occurrence rate in men was almost twice as much as in women and the case fatality rate was the same as the occurrence rate among men and women. 125 In addition, Channappanavar et al had reported that male mice were more susceptible to SARS-CoV infection compared with age-matched female mice. However, the mortality was increased in female mice when the ovariectomy was done or the estrogen receptor antagonist was given. 126 Wei et al 127 also found that serum levels of prolactin, follicle-stimulating hormone, and luteinizing hormone of ZHANG AND LIU | 485 SARS patients were significantly higher than those of control groups, while estradiol (E2), pregnancy hormone, and thyroid-stimulating hormone were considerably lower than those of normal controls.

Interestingly, estrogenic compounds had been found to reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors. 128 In addition, resveratrol, a phytoestrogen from grape seeds and red wine, had been reported to be a potent anti-MERS agent in vitro. 129 Therefore, 17β-Estradiol or phytoestrogen could also be an alternative option to be considered for the treatment of COVID-19.

Mucroporin-M1 is a scorpion venom-derived peptide and has broadspectrum virucidal activity against many viruses including measles, influenza H5N1 viruses, and SARS-CoV. 130 Therefore, this peptide could also be used for the treatment of COVID-19 infection as well as the new drug design to target COVID-19.

In this review, we summarize all the potential interventions for Regarding short-term protection and prevention of viral infection, passive immunotherapy should not be neglected. 135 Monoclonal antibody therapy is one of the best forms of passive immunotherapy.

A human IgG1 mAb, CR3014, had been generated and it had been found to be reactive with whole inactivated SARS coronavirus. In addition, CR3014 could be used as prophylaxis for SARS coronavirus infection in ferrets. 136 However, CR3014 was found to be able to block the interaction in parent SARS-CoV strain, but not in escape variants. This led to the ineffectiveness of CR3014 to prevent infection in humans. CR3022 was another monoclonal antibody and it had been found to neutralize CR3014 escape viruses. 136 The combination of CR3014 and CR3022 had also been reported to have the potential to control immune escape. 135 However, the clinical trial of CR3022 with CR3014 had never been tried due to the high cost of manufacturing.

Convalescent plasma can also be called passive immunotherapy.

It is usually chosen when there are no specific vaccines or drugs available for emerging infection-related diseases. 137 Arabi et al had tested the feasibility of convalescent plasma therapy as well as its safety and clinical efficacy in critically ill MERS patients. They found that convalescent plasma had an immunotherapeutic potential for the treatment of MERS-CoV infection. 138 In addition, convalescent plasma from recovered SARS patients had also been reported to be useful clinically for treating other SARS patients. 139, 140 Importantly, the use of convalescent plasma or serum was also suggested by the World Health Organization under Blood Regulators Network when vaccines and antiviral drugs were unavailable for an emerging virus.

In summary, these findings suggest that the current children's RNA-virus-related vaccines are the best alternative methods to be used to vaccinate the uninfected people and health care workers.

Convalescent plasma should be routinely used for the treatment of COVID-19 infected critically sick patients if it is available. The avian IBV vaccine is also another choice for clinical trials if its safety has been approved in monkeys. Therefore, we suggest that all the potential interventions be implemented to control the emerging COVID-19 if the infection is uncontrollable.

The authors declare that there are no conflict of interests.

Yunhui Liu http://orcid.org/0000-0002-9920-9933

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Middle East respiratory syndrome

New SARS-like virus in China triggers alarm

A novel coronavirus from patients with pneumonia in China

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Recent advances in the detection of respiratory virus infection in humans

Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan

Selenium, selenoproteins and viral infection

Importance of vitamin A deficiency in pathology and immunology of viral infections

Vitamin A and immunity to viral, bacterial and protozoan infections

Vitamin A supplements ameliorate the adverse effect of HIV-1, malaria, and diarrheal infections on child growth

Effects of dietary vitamin A content on antibody responses of feedlot calves inoculated intramuscularly with an inactivated bovine coronavirus vaccine

Epithelia-damaging virus infections affect vitamin A status in chickens

Retinoids inhibit measles virus through a type I IFN-dependent bystander effect

Riboflavin (vitamin B-2) and health

Inactivation of Middle East respiratory syndrome coronavirus (MERS-CoV) in plasma products using a riboflavin-based and ultraviolet light-based photochemical treatment

C/EBPepsilon mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice

Nicotinamide exacerbates hypoxemia in ventilator-induced lung injury independent of neutrophil infiltration

The effect of ascorbic acid on infection chick-embryo ciliated tracheal organ cultures by coronavirus

Nutrients and their role in host resistance to infection

Vitamin C intake and susceptibility to pneumonia

Vitamin D insufficiency among free-living healthy young adults

Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease

Acute phase response elicited by experimental bovine diarrhea virus (BVDV) infection is associated with decreased vitamin D and E status of vitamin-replete preruminant calves

Vitamin E metabolic effects and genetic variants: a challenge for precision nutrition in obesity and associated disturbances

Vitamin E deficiency intensifies the myocardial injury of coxsackievirus B3 infection of mice

Increased virulence of coxsackievirus B3 in mice due to vitamin E or selenium deficiency

Macrophage-derived extracellular vesicles induce long-lasting immunity against hepatitis C virus which is blunted by polyunsaturated fatty acids

Plasma fatty acid levels in patients with acquired immune deficiency syndrome and in controls

The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza

Anti-HCV activities of selective polyunsaturated fatty acids

Selenium and human health

Micronutrients and host resistance to viral infection

Review: micronutrient selenium deficiency influences evolution of some viral infectious diseases

Selenium deficiency increases the pathology of an influenza virus infection

Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates

Combined adjuvant effect of ginseng stem-leaf saponins and selenium on immune responses to a live bivalent vaccine of Newcastle disease virus and infectious bronchitis virus in chickens

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Zinc deficiency

Zinc supplementation for the treatment of measles in children

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Childhood iron deficiency anemia leads to recurrent respiratory tract infections and gastroenteritis

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Flavonoids from pterogyne nitens inhibit hepatitis C virus entry

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Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors

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Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

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Nitric oxide

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An overview on severe acute respiratory syndrome (SARS)

Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus

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Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors

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