key: cord-0881309-z4hc9yhb authors: Jawaid Akhtar, Md title: COVID19 inhibitors: A prospective therapeutics date: 2020-06-17 journal: Bioorg Chem DOI: 10.1016/j.bioorg.2020.104027 sha: ddc44c73ad93311b5d0e367be63387319d711f41 doc_id: 881309 cord_uid: z4hc9yhb Abstract The inhibition of viral targets might provide new therapies for coronavirus disease abbreviated as COVID-19. The rational drug design identified as much of the recent discoveries of potent drugs molecule against any targets. This results in an improvement in bindings for better potency and selectivity. The drugs containing ethanolamine/propylamine fragments along with heterocycles have shown potential antiviral results. Similarly, there is the possibility of controlling the COVID-19 infection by nucleotide analogues. Here we also highlight drugs ACEIs/ARBs inhibitory discussing both their advantages and disadvantages. The class of compounds/antibodies inhibiting interleukin-6 works in antirheumatoid drugs are found useful in alleviating overactive inflammatory responses in the lungs of the patient. These inclusion based approaches counter some of the side-effects associated with the heterocycles and also potentiate the efficacy of the molecules. In this review article, design strategies for some of the drugs effective against SARS-CoV-2 are represented. The review also focuses on the listing of drugs that are currently testing under clinical trials for the COVID-19 virus with their mechanism of action. This conversation undertakes the opportunity to do a bit for the newer researchers working in this arena. Viruses are non-living having genetic material and an outer lipid envelope. The viral disease continued to be a serious issue to public health. The CoVs have become the major pathogens of emerging respiratory disease outbreaks. In the past major epidemic severe acute respiratory syndrome coronavirus (SARS-CoV) Because of its similarity with SARS outbreak (SARS-CoVs), it is known as SARS-CoV-2 [1] . SARS-CoV-2 is placed as a 7 th member of the coronavirus family infecting human after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Bats have been linked with these highly pathogenic viruses (SARS-CoV and MERS-CoV) and other hemorrhagic ebola, Marburg filoviruses, and paramyxoviruses such as Nipah virus [2] . SARS-CoV-2 is a novel coronavirus belonging to βgenus infecting mammals and humans. There is a 94.6% amino acid similarity between SARS-CoV-2 and SARS-CoV which suggests for the origin of these coronaviruses from the same species. Further, a similarity of 96% genome between the SARS-CoV-2 and bat sarbecovirus sampled from Rhinolophus affinis horseshoe bat in Yunan province (2013) Bat-CoV (RaTG13) indicates a homologous relationship between them [3] [4] . This makes to confirm that current outbreak of COVID-19 may have bat origin. A recent study in Myanmar was carried by Valitutto et al to identify coronavirus in bats. Free-ranging bats were captured and rectal and oral swabs were collected and screened for coronavirus by reactive consensus conventional polymerase chain reaction. Three novel alphacoronavirus, three novel beta coronavirus and one known alphacoronavirus were detected in bats in Myanmar [2] . The spike protein having receptor-binding domain (RBD) is the most variable part in the coronavirus genome. Two possible origins for the SARS-CoV-2 is concluded by: One possible conclusion is drawn on the basis of the previous outbreak (i.e. human is infected by virus after exposure to civets and camels for SARS and MERS). Thus, it is reasoned that SARS-CoV-2 is also evolved into a pathogenic state by natural selection first in the non-human host and then spill into humans. Another source of origin is that non-pathogenic viruses in animals jump to humans and then evolved into the current pathogenic states. The SARS-CoV-2 has very similar RBD to the earlier coronavirus from pangolins, armadillo-like mammals. It could have been transferred from Pangolins to humans with in-between hosts such as civets and ferrets [5] . As on April 15 2020, there were more than 19.5 lakh cases and total death crosses more than 1.26 lakh worldwide. Among the most seriously affected countries are US, Spain, Italy and France [6] . COVID19 contains spike protein in the form of a crown (that's why named corona) to have attachment to the specific receptors present in the epithelial cell and then multiply. There are several strategies to overcome viral infection; either blocking the receptors to avoid the entry of viruses, destroy the machinery i.e prevention of replication, prevention of release or shredding and activate the natural killer cells to kill the infected cells. Under each category, effective drugs are available [7] [8] [9] . Research efforts are focused on the influenza neuraminidase molecular targets, one of two major glycoproteins located on the influenza virus membrane envelope. This enzyme is responsible for the cleavage of terminal sialic acid residues from glycoconjugates and is essential for virus replication and infectivity [10] , other hot areas include developing human neutralizing antibodies/monoclonal antibodies, virus-neutralizing antibodies, searching a library of compounds. The COVID-19 caused disastrous effects leading to lakhs of death and affecting millions of people worldwide. It causes severe pneumonia and currently, no available antiviral therapy exists to treat SARS-CoV2 patients. A lot of clinical trials are undergoing to develop more targeted and effective viral drugs and vaccines and may take years [11] . However, some existing drugs were found to alleviate the symptoms of COVID-19 and are discussed. Chloroquine (CQ), a 4-aminoquinoline compound, has been used for the prophylaxis and treatment of malaria. Chloroquine now becomes ineffective for the prevention or treatment of malaria caused by P. falciparum. Hydroxychloroquine (HCQ) is an analogue of CQ in which one of the N-ethyl substituents of CQ is β-hydroxylated. HCQ is preferred over CQ when high doses are required because of the lower level of ocular toxicity of HCQ than of CQ. HCQ is metabolized in the liver into three active metabolites, Desethylchloroquine (DCQ), Desethylhydroxychloroquine (DHCQ) and bisdesethylchloroquine (BDCQ) [12] . Among the three DHCQ being the major metabolite. The absorption half-life was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days [13] . Also, Desethylhydroxychloroquine is implicated early or established stage inflammatory diseases with the advantages that individual escapes retinal toxicity [14] . Clinical trials of hydroxychloroquine (used as effective antimalarial) treatment for COVID-19 pneumonia are underway in China (NCT04261517 and NCT04307693) [15] . The drugs chloroquine/hydroxychloroquine has shown positive results in COVID-19 positive patients. Further, it also suggests for the mechanism of interfering SARS-nCov-2 replication in some of the in-vitro studies [16] . Figure 1 showing the metabolized product of hydroxychloroquine active against coronavirus. Pyrimidine coupled with standard care [19] . It also inhibits influenza strains resistant to current antiviral drugs, and shows a synergistic effect in combination with oseltamivir, thereby expanding influenza treatment options [20] . In one of the trials testing favipiravir with interferon in Shenzhen, results showed that patients treated with the combination had significantly reduced the duration of symptoms, as measured by viral load chest imaging, vs. a control group. In another study, clinical recovery rates were higher for COVID-19 patients treated with favipiravir vs. those in a control group [21] . [22] . The drug is found to bind and inhibit the active site of neuraminidase enzymes required by the viral particle to release virions progeny. It thus reduces viral replication and reduces the viral load [23] . However, based on Cochrane review 2014, Osteltamivir does not reduce hospitalizations neither reduces the complications of influenza [24] . Further, it was also used in one of phase III clinical trials for COVID-19 in combination with ritonavir and protease inhibitor ASC09F [25] [26] . [29] . In the case of lopinavir, the predominant site of metabolism was found to be the carbon-4 of the cyclic urea moiety (propanolamine derived), with subsequent secondary metabolism occurring on the diphenyl core moiety [30] . Figure 1 shows the metabolized product of drug Ritonavir/Lopinavir effective against coronavirus. This drug is in phase III clinical trials in countries with a high prevalence of COVID19. Remdisiviral a broad-spectrum antiviral drugs target viral proteins and prevents copying, replication and decrease in viral production [31] . They are adenosine analogues and in some virus it insert into the viral chain and induces irreversible chain termination [32] . After its conversion into active triphosphate form the drugs, it competes for the adenosine triphosphate (natural nucleotide required for RNA synthesis) required for replication and thus terminate the RNA synthesis [33] Galidesivir is adenosine analogues that block RNA polymerase. RNA polymerase is involved in the viral replication process. Galidesivir is activated to active triphosphate form by cellular kinases and gets incorporated into the growing chains of RNA strand leading to chain termination. A Galidesivir drug is undergoing clinical trials and part 1 of the trial includes 24 hospitalized with three sequential cohorts of eight patients each. The patient receives intravenous (IV) galidesivir (n=6) and placebo (n=2) every 12 h for 7 days. After this dose regimen will be selected for part 2 of the trial based on the results of part 1 including safety, viral load, reduction in respiratory tract secretion and improvements in COVID-19 infection and mortality. A total of 42 hospitalized patients of COVID-19 will include in part 2 of the trial and will be randomized into 2:1 to receive IV galidesivir and placebo. The patient will remain hospitalized or release after symptoms allow the release and will be observed for mortality till day 56 [38] . Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and (SARS-CoV) uses the receptor angiotensin-converting enzyme (ACE) 2 for entry into target cells. which is specifically highly expressed by epithelial cells in oral mucosa [39] [40] [41] . It is also argued that ACE2 could be directly inhibited by ACE inhibitors but ACE2 functions as a carboxypeptidase and is not inhibited by clinically prescribed ACE inhibitors [42] . ACE2 are increased in patients with hypertension or diabetes, and levels are further increased by different drugs, including ACEIs (Angiotensin-converting enzyme inhibitors e.g. captopril) and ARBs (Angiotensinreceptor blockers, e.g. Losartan) Figure 5 [40] . Thus it increases the risk for the severity of SARS-CoV2. Conversely, some researchers also tell about benefits to the patient taking these mentioned drugs. They justified it as the upregulating of ACE2 will have benefits as it has vasodilatory and anti-inflammatory properties after ACE2 converts angiotensin II to angiotensin (1-7) [43] . There is preclinical studies in mice that justified that ARB treatment reverses lung injury through SARS-CoV-2 invasion by decreasing ACE2. Another way preclinical data also tells about the increase in ACE2 support for an effective treatment for viral lung injury. These preclinical studies do not support in clinical trials with the human subjects. One studies tells that it neither benefits by increasing ACE2 (done by infusing ACE2) nor ACEIs or ARBs decreases the severity by SARS-CoV-2 lung injury [44] . There is no such observational studies to confirm whether these ACEIs or ARBs could potentially harm or benefits the patient. Several European and American cardiology societies dispel this misinformation and advised not to stop these RAAS antagonists unless advised by physician [45] [46] . suggested for increase in inflammatory response through increased interleukin-6 and causes the death of a patient suffering from community-acquired pneumonia [47] . More details of the drug tocilizumab is also discussed in antibodies under miscellaneous section.  Kevzara (sarilumab) -is also a whole human monoclonal antibody and work against Interleukin-6 receptors. This drug is FDA approved for rheumatoid arthritis. The drug is tested in COVID patients as IL-6 may play a role of inhibiting overactive inflammatory response in the lungs of severely and critically ill patients. It showed an improvement rapidly reducing fevers and the patient requires less oxygen support [48] [49] . Phase I and phase II study was already carried out inpatient with COVID-19. Roxolitinib is an inhibitor of JAK ½ and is associated with multiple cellular signals including IL-6. The study intended to stop the dysregulated immune response caused by COVID-19. This drug work as an immunomodulator decreasing the respiratory or pneumonia symptoms caused by dysregulated immune response. It showed a good recovery of pneumonia in its primary outcome [50] [51] .  Calquence (acalabrutinib):-The drug is used for the treatment of lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) (blood cancer) and is Bruton's tyrosine kinase (BTK) inhibitor. This was found to be useful in later stages of COVID-some clinical benefits to the patient suffering from advanced lung diseases, but now it will be very early to say that it will provide benefits to the patients for recovery [52] [53] . Baricitinib is small molecule inhibitors and has potential effects in inhibiting JAK1 and JAK2 mediated cytokine release and thus may be regarded as helpful in inhibiting coronavirus to infect the cells Figure 6 . The drug was approved for the treatment of rheumatoid arthritis, works by interfering STAT proteins and now undergoing clinical trials for COVID-19. This drug is used in combination with other antivirals as it has no potential drug-drug interaction [54] [55] . Convalescent plasma therapy is used for recovery of SARS patients whose condition worsens despite all possible treatments. There is a report available that lower hospital stay and mortality rate is observed for the patient in convalescent plasma therapy than who are not treated with plasma therapy. The therapy is effective as antibodies from the convalescent therapy reduce the viral load and treat viremia. Viremia is in the highest peak in the first 10-14 days and primary immune response develops for virus clearance. Plasma therapy is more effective in the early stages of the disease. There is evidence that convalescent plasma may be used for the treatment of coronavirus patients without severe adverse effects. However there is a continuous need to evaluate for safety and efficacy of convalescent plasma therapy [57] . patients with high cytokine storms [64] . Zhang et al showed through many data that cytokines storms in many patients are the cause of death and treatment to reduce these cytokines storms save COVID-19 patients. IL6 causes the release of cytokines and inhibition of IL6 pathway by the use of drugs such as tocilizumab blocks the IL6 pathway. Thus it was concluded tocilizumab to be effective drugs for patients with severe COVID-19 [65] . The Based on the most common drugs given to reduce the infection caused by SARS-CoV2, here we postulated that some of the drugs have the common features of ethanolamine/propylamine group present or activated to have that fragment present to decrease the severity of infection. One property of monoethyl amine is under carbon dioxide (hypoxia condition; carbonic acid formation) carbamate formation takes place which can be cyclized into oxazolidin-2-one [71] . The oxazolidin-2-one is known to possess antibacterial properties and is present in many antibacterial compounds such as Linezolid, Posizolid, Tedizolid, Redezolid (antibacterial), Cycloserine (antitubercular) and Contezolid (phase III) and Rivaroxaban approved by FDA for venous thromboembolism [72] . Most of the cases the immune system recover and kill the infected cells. Sometimes it becomes critical as lungs protective linings is gone and the patient further gets infected with bacteria and pneumonia occurs. The patient requires ventilator support for breathing. Bacteria multiplied and enter the bloodstream and death occurs. Preexposure prophylaxis and postexposure prophylaxis (PEP) with antimicrobial drugs are effective in preventing illness before potential exposure or after documented exposure to a variety of microbial pathogens, and in reducing the risk of secondary spread of infection [73] . Another major area covered in this review is antiviral drugs and the possibility of developing more potent inhibitors with better selectivity. Targetting through ACEIs/ARBs offers an interesting prospects for inhibiting virus entry. In the future, this could provide a successful design of potent inhibitors for coronavirus toppling its considerable risk. The growing benefits of interleukin inhibitors can be a step towards the right direction against coronavirus, but the prolems is that it is not more advantageous to the early detected patient with coronavirus. Hence the use is limited to the patient severely affected with lung infection. Convalescent plasma, antibodies and anticoagulant therapy lessen the mortality rate in severe COVID-19 patients, but it is quite early to predict the safety and efficacy of these therapy in SARS-CoV-2 infected patients. Drug discovery is a challenging process due to the complexity of the biological system. The authors declare no conflicts of interest, financial or otherwise. 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