232 | Journal of Molecular Cell Biology (2021), 13(3), 232–236 doi:10.1093/jmcb/mjab002 Published online January 25, 2021 Perspective Available drugs and supplements for rapid deployment for treatment of COVID-19

Danielle Cicka1 and Vikas P. Sukhatme2,*

1 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA 2 Department of Medicine, Department of Hematology and Medical Oncology, Morningside Center for Innovative and Affordable Medicine, Emory University Downloaded from https://academic.oup.com/jmcb/article/13/3/232/6119634 by guest on 24 September 2021 School of Medicine, Atlanta, GA, USA * Correspondence to: Vikas P. Sukhatme, E-mail: [email protected]

Effective treatment for COVID-19 Introduction therapeutic discovery process in a crisis, remains elusive, though urgently needed There is an urgent need for effective saving time, money, and lives. in the current pandemic. Repurposing treatments for COVID-19, the clinical To harness the valuable information marketed therapies may be an effective manifestation of SARS-CoV-2 infection. that researchers have produced in the strategy for finding treatments quickly and Over 83 million cases of COVID-19 and face of previous outbreaks of coronavi- recently, in vitro and clinical testing of over 1.8 million deaths due to COVID-19 ruses and in the current pandemic, we such therapies against severe acute respi- have been documented worldwide by have compiled the scientific literature on ratory syndrome coronavirus 2 (SARS-CoV- early January 2021 (https://www.world marketed therapies for the treatment of 2)hasskyrocketed.However,notallmar- ometers.info/coronavirus/). COVID-19 coronaviruses to prioritize therapies for keted drugs showing in vitro efficacy can spread through asymptomatic or further testing. This includes in vitro could achieve therapeutic concentrations symptomatic patients who may present half maximal inhibitory concentrations in humans and discernment of drugs that with a wide variety of symptoms includ- (IC50s), animal studies, human studies, have favorable pharmacokinetic proper- ing dyspnea, cough, fatigue, and fever potential mechanisms of action, phar- ties can save time and resources for fu- (Grant et al., 2020; Wiersinga et al., macokinetic data, and in silico data, if ture studies. Here, we compile marketed 2020). The fatality rate is difficult to cal- available. Our analysis is different from therapies, including supplements, having culate and depends on many factors in- previous works such as Arshad et al. antiviral activity with in vitro, in vivo,and/ cluding age, comorbid conditions, and (2020), as it focuses on marketed thera- or clinical data against a and b coronavi- gender, but is estimated to range from peutics and supplements with reported ruses into tables, alongside their pharma- 0.03%to30% and >30% mortality in blood concentrations at least five times cokinetic properties. We point to several the intensive care unit (Quah et al., (5) higher than their IC50s in coronavi- drugs or supplements available for imme- 2020; Wiersinga et al., 2020). Current rus system and compiles clinical, in vivo, diate repurposing because they have treatments include supportive care, in vitro, and in silico data. achievable blood concentrations in dexamethasone, and remdesivir for hos- humans well above their inhibitory con- pitalized patients (Wiersinga et al., centrations against coronaviruses. This 2020). New treatments are urgently Materials and methods compilation may contribute to the imple- needed for both inpatient and outpatient Coronaviruses are classified into four mentation of rapid future studies by nar- cases. However, the development of genera: a, b, c, and d. All seven corona- rowing the vast number of marketed novel pharmaceuticals from preclinical viruses known to cause respiratory infec- drugs reported for potential efficacy studies to Phase III clinical trials is often tions in humans fall into the a or b against SARS-CoV-2 on the basis of their a long process, wrought with failures. genera, with SARS-CoV-2, SARS-CoV-1, pharmacokinetic properties and pub- Alternatively, marketed drugs may pro- and Middle East respiratory syndrome lished coronavirus data. vide a favorable starting point for treat- coronavirus (MERS-CoV) as members of ment discovery, since there are already the b coronavirus genera (Ye et al., indications of their safety, toxicity, and 2020). Given sequence and biological pharmacokinetic profiles in humans. similarities between the a and b corona- This is an Open Access article distributed under the terms of the Creative Commons Attribution License Maintaining high ethical standards and viruses, identifying and prioritizing mar- (http://creativecommons.org/licenses/by/4.0/), stringent criteria for evaluating efficacy keted drugs that have in vitro or in vivo which permits unrestricted reuse, distribution, and activity against these coronaviruses is a reproduction in any medium, provided the original of repurposing drugs is crucial, which, work is properly cited. when done correctly, may expedite the reasonable approach, while noting some

VC The Author(s) (2021). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS. Available drugs and supplements for rapid deployment for treatment of COVID-19 | 233

Table 1 The highest level of data available for drugs or supplements acting on the viral life cycle with blood concentrations greater than 5 their IC50s against SARS-CoV-2. Drug or Human data in coronavirus patients Animal data Cell culture data (IC50 in lM) supplement name Baicalin NA NA SARS-CoV-23CLpro inhibition IC50 ¼ 6.41 (Su et al., 2020) Dalbavancin NA SARS-CoV-2 mouse model treated with See Supplementary Table S1 dalbavancin (130 mg/kg intraperito- neal on Day 0) and SARS-CoV-2 rhe- sus macaque model treated with dalbavancin (60 mg/kg on Day 0 and 30 mg/kg on Day 4) showed lower vi- ral load and reduced histopathologi-

cal injury compared to control (Wang Downloaded from https://academic.oup.com/jmcb/article/13/3/232/6119634 by guest on 24 September 2021 et al., 2020a) Dipyridamole Prospective, open-label, randomized, controlled NA See Supplementary Table S1 study of COVID-19 patients showed those receiving dipyridamole treatment (50 mg 3/day) had higher clinical remission rates, decreased D-dimer, and increased lymphocytes and platelets compared to control patients (Liu et al., 2020) Eltrombopag NA NA SARS-CoV-2 IC50 ¼ 8.27 (Vero cells) (Jeon et al., 2020) SARS-CoV-2 IC50 ¼ 8.38 (Calu-3 cells) (Ko et al., 2021) Favipiravir Prospective, open-label, randomized, controlled See Supplementary Table S1 See Supplementary Table S1 study of COVID-19 patients receiving favipiravir (1800 mg 2/day on Day 1, then 800 mg 2/day) showed shorter time to clinical improvement com- pared to control (Udwadia et al., 2020) Prospective, open-label, randomized, controlled study of COVID-19 patients showed those receiving favi- piravir (1600 or 2200 mg on Day 1, then 600 mg 3/day) had no significant reduction in viral load compared to control (Lou et al., 2020) Mycophenolate NA See Supplementary Table S1 Mycophenolate acid against SARS-CoV-2 mofetil/myco- IC50 ¼ 0.87 (Vero/TMPRSS2 cells) (Kato et al., phenolic acid 2020) Mycophenolic acid against SARS-CoV-2 IC50 ¼ 0.101 (Vero E6 cells) (Wan et al., 2020) Nafamostat Case reports and retrospective, uncontrolled study of NA See Supplementary Table S1 COVID-19 patients treated with nafamostat (Doi et al., 2020a, b; Jang and Rhee, 2020; Osawa et al., 2020) Nitazoxanide See Supplementary Table S1 NA SARS-CoV-2 IC50 ¼ 2.12 (Vero E6 cells) (Wang et al., 2020b) Remdesivir Prospective, randomized, controlled trial of COVID-19 See Supplementary Table S1 See Supplementary Table S1 patients showed those receiving remdesivir (200 mg intravenous on Day 1, then 100 mg/day) had faster time to clinical improvement, but not statistically sig- nificantly different compared to control (Wang et al., 2020c) Prospective, randomized, controlled study of COVID-19 patients showed those treated with remdesivir (200 mg intravenous on Day 1, then 100 mg/day) had shorter time to recover compared to control (Beigel et al., 2020) Sulfadoxine NA NA SARS-CoV-2 IC50 ¼ 35.37 (Vero E6 cells) (Touret et al., 2020) Teicoplanin Retrospective, uncontrolled study of hospitalized NA See Supplementary Table S1 COVID-19 patients receiving teicoplanin (600 mg/ day) (Ceccarelli et al., 2020)

NA, not available. 234 | Cicka and Sukhatme distinct similarities between SARS-CoV-2 other coronaviruses. If the highest level Limitations and SARS-CoV-1 (Jaimes et al., 2020; Ye of evidence for a drug or supplement did We focused on compiling a useful, but et al., 2020). Therefore, to obtain our ini- not show any efficacy, the therapy was simple table on potential drugs for repur- tial list of therapies, we conducted not included. Supplementary Table S1 posing for COVID-19, utilizing IC50s and PubMed and Google Scholar searches includes extended data of the drugs and known achievable blood concentrations. using keywords such as ‘coronavirus’, supplements in Table 1 against any a or However, this strategy has some limita- ‘SARS2’, ‘COVID-19’, ‘SARS-CoV-2’, b coronavirus, including SARS-CoV-2, tions and we encourage reading of the ‘repurposed drugs’, ‘treatment’, and along with the reported blood concentra- primary literature for further information. ‘therapy’. tions used for the selection of these In particular, these tables do not contain We compiled a list of available small drugs and supplements. Supplementary an exhaustive compilation of pharmaco- molecules that have been tested in vitro Table S2 includes drugs and supple- kinetic properties of these therapies for Downloaded from https://academic.oup.com/jmcb/article/13/3/232/6119634 by guest on 24 September 2021 against coronaviruses into tables. We ments without available data against simplicity and a more complete evalua- further included an achievable maximal SARS-CoV-2 or COVID-19 but showing tion of the pharmacokinetic properties of concentration (Cmax) in blood or plasma achievable blood concentrations at least these drugs should be done prior to fur- regardless if steady state is reached or 5 higher than their IC50s against other ther studies. For example, the achiev- lowest concentration before next dose coronaviruses. The drugs in these tables able concentration in the lung may be (Ctrough) obtained in clinical studies of may be the most promising candidates different from that in the peripheral blood, the reported concentration in the healthy human subjects or in studies of for further in vitro, in vivo, or clinical the dosing and treatment regimen in blood may not reflect the fraction of drug evaluation of their activity against coro- humans as generally indicated for the unbound in plasma, and the variable naviruses. They are arranged in alpha- drug. In order to enhance chances of ef- and transient nature of Cmax does not betical order in each table. Values were ficacy in humans, drugs with reported depict tissue exposure to a drug over estimated if necessary and indicated by blood concentrations at least 5 greater time. Route of administration, drug–drug ‘’ prior to the value. Combination thera- than IC50 values obtained in cell culture interactions, clinical characteristics of pies are in orange text. against coronaviruses were further se- patients, and dose scheduling may alter lected. If a drug is rapidly metabolized the achievable concentrations in the and the blood concentration of the me- lung or peripheral blood as well. Some Results tabolite was available, this was used for drugs, notably mycophenolate mofetil, From our compilation of the literature comparison to the IC50s and indicated nitazoxanide, and remdesivir, are on marketed drugs and supplements in column 2 of Supplementary Table S1. quickly metabolized and studies did not with efficacy against coronaviruses, sev- Recognizing the variation between ex- always determine whether the parental eral candidates stand out as fitting our perimental IC50s, if one experimental compound or metabolite were responsi- criteria for favorable pharmacokinetic IC50 fitted this criterion, the drug was ble for antiviral activity in vitro, which properties. These candidates with considered a promising candidate. If complicates determining whether their reported activity against SARS-CoV-2 are SARS-CoV-2 data were not available, IC50s are achievable in humans. Further, 1 IC50s against other coronaviruses were listed alphabetically in Table . clinical trials involve the study of used for selection. We compiled the However, as shown in Supplementary patients with a complex set of treat- 2 studies testing efficacy of these candi- Table S , oxaprozin and telavancin ments, comorbidities, and outcomes, dates against coronaviruses including showed activity against other coronavi- which are not captured in this table but 5 clinical data, in vivo studies, in vitro ruses with blood concentrations could provide valuable insight into 50 studies, in silico studies, and potential greater than their IC s, but no peer- mechanisms of action or differences in mechanisms of action. reviewed data against SARS-CoV-2 have effectiveness. These tables also do not We have assembled the information yet been reported to our knowledge. contain information on ongoing clinical on each drug into three tables: Table 1 A brief commentary on the drugs is trials as the focus is on reported data for and Supplementary Tables S1 and S2. available in Supplementary Table S3 in- these therapies. Additionally, supple- Table 1 includes the highest level of cluding their indications and common ments are not FDA approved and have available data of drugs and supplements side effects that typically occur at an in- not necessarily been studied in clinical against SARS-CoV-2 or COVID-19.We cidence of 1% or greater according to trials. These small molecules should be chose the highest level of evidence to be Drugs.com (https://www.drugs.com/), further evaluated for their safety profiles randomized, double-blinded, controlled unless otherwise noted. and pharmacokinetic parameters if trials of COVID-19 patients, followed by Based on the route of administration, needed. other types of clinical trials for COVID-19 toxicity profile, and therapeutic index, Also, IC50 does not give a complete patients, in vivo SARS-CoV-2 studies, these drugs would be more or less ap- picture of the effectiveness of a drug in vitro studies against SARS-CoV-2, and propriate in the outpatient or inpatient against coronavirus. Though we chose then clinical trials and in vitro studies on setting. drugs with IC50s at least 5 lower than Available drugs and supplements for rapid deployment for treatment of COVID-19 | 235 their known achievable blood concentra- against coronaviruses along with phar- heparin during extracorporeal membrane oxy- tions, the dose–response curve and macokinetic data. We have identified genation. Acute Med. Surg. 7,e585. Grant, M.C., Geoghegan, L., Arbyn, M., et al. IC90 for each drug may paint a more clin- several candidate small molecules with (2020). The prevalence of symptoms in ically relevant picture for dosage. favorable pharmacokinetic properties for 24,410 adults infected by the novel coronavi- Further, IC50s against coronaviruses dif- further evaluation for repurposing rus (SARS-CoV-2; COVID-19): a systematic re- fer based on assay. There are many var- against SARS-CoV-2. This assembly may view and meta-analysis of 148 studies from 9 15 0234765 iations of in vitro assays to determine a be beneficial for researchers comparing countries. PLoS One ,e . Hoffmann, M., Mo¨sbauer, K., Hofmann-Winkler, small molecule’s efficacy against viruses the vast amount of data available for the H., et al. (2020). Chloroquine does not inhibit utilizing different readouts, conditions, therapeutic potential of available drugs infection of human lung cells with and various viral strains. Some drugs for further studies on treatments for SARS-CoV-2. Nature 585, 588–590. may have effects both on the viral life cy- COVID-19. Jaimes, J.A., Andre´, N.M., Chappie, J.S., et al. 2020 Downloaded from https://academic.oup.com/jmcb/article/13/3/232/6119634 by guest on 24 September 2021 cle and on the immune response and [Supplementary material is available at ( ). Phylogenetic analysis and structural 2 Journal of Molecular Cell Biology online. modeling of SARS-CoV- spike protein reveals therefore may have different effects an evolutionary distinct and proteolytically in vivo. Many of the IC50s listed are We would like to thank Dr Joshy Jacob at sensitive activation loop. J. Mol. Biol. 432, obtained through experiments that do Emory University for useful conversations 3309–3325. not utilize primary human lung cells and and insights. D.C. was supported by NIH Jang, S., and Rhee, J.-Y. (2020). Three cases of it has been noted in previous studies training grant T32-GM008602. V.P.S. treatment with nafamostat in elderly patients with COVID-19 pneumonia who need oxygen 50 has an interest in repurposing of drugs that the IC may vary markedly based therapy. Int. J. Infect. Dis. 96, 500–502. on cell lines used (Hoffmann et al., as director and cofounder of Jeon, S., Ko, M., Lee, J., et al. (2020). 2020). Animal and human studies are the Morningside Center for Innovative Identification of antiviral drug candidates needed to determine the true efficacy of and Affordable Medicine, cofounder against SARS-CoV-2 from FDA-approved drugs. 2 of GlobalCures, and member of the Antimicrob. Agents Chemother. 64, these drugs against SARS-CoV- . 00819 20 Scientific Advisory Board of The e - . Kato, F., Matsuyama, S., Kawase, M., et al. Anticancer Fund. V.P.S. conceived of the Speculations (2020). Antiviral activities of mycophenolic We speculate that some of these small presented idea and supervised the proj- acid and IMD-0354 against SARS-CoV-2. molecules may be candidates for further ect. D.C. completed the literature review Microbiol. Immunol. 64, 635–639. 2021 research as therapies for COVID-19,since and tables. Both authors discussed Ko, M., Jeon, S., Ryu, W.-S., et al. ( ). Comparative analysis of antiviral efficacy of 50 results and contributed to the writing of their IC s are well below their achievable FDA-approved drugs against SARS-CoV-2 in the final manuscript.] blood concentrations. Combining drugs human lung cells. J. Med. Virol. 93, with differing mechanisms may also show 1402–1408. synergistic effects and reduce emergence Liu, X., Li, Z., Liu, S., et al. (2020). Potential thera- peutic effects of dipyridamole in the severely of resistance. Further, COVID-19 is a com- References Arshad, U., Pertinez, H., Box, H., et al. (2020). ill patients with COVID-19. Acta Pharm. Sin. B plex disease with a strong immune com- Prioritization of anti-SARS-Cov-2 drug repur- 10, 1205–1215. ponent (Blanco-Melo et al., 2020; Qin posing opportunities based on plasma and Lou, Y., Liu, L., Yao, H., et al. (2020). Clinical out- et al., 2020). Therefore, we speculate that target site concentrations derived from their comes and plasma concentrations of baloxavir a combination of host-directed and viral- established human pharmacokinetics. Clin. marboxil and favipiravir in COVID-19 patients: 108 775 790 an exploratory randomized, controlled trial. directed therapies with achievable inhibi- Pharmacol. Ther. , – . Beigel, J.H., Tomashek, K.M., Dodd, L.E., et al. Eur. J. Pharm. Sci. 157, 105631. tory concentrations in humans may be (2020). Remdesivir for the treatment of Osawa, I., Okamoto, K., Ikeda, M., et al. (2020). particularly effective treatment for COVID- Covid-19—preliminary report. New Engl. J. Dynamic changes in fibrinogen and D-dimer 19. Timing of these therapeutic combina- Med. 383, 994. levels in COVID-19 patients on nafamostat tions may be important as the immune re- Blanco-Melo, D., Nilsson-Payant, B.E., Liu, W.C., mesylate. J. Thromb. Thromb. https://doi.org/ et al. (2020). Imbalanced host response to 10.1007/s11239-020-02275-5 sponsemayvarythroughouttheclinical SARS-CoV-2 drives development of COVID-19. Qin, C., Zhou, L., Hu, Z., et al. (2020). 2020 diseasecourse(Shi et al., ). Cell 181, 1036–1045.e9. Dysregulation of immune response in patients Additionally, toxicities of these drugs indi- Ceccarelli, G., Alessandri, F., d’Ettorre, G., et al. with coronavirus 2019 (COVID-19) in Wuhan, vidually and in combination will need to (2020). Is teicoplanin a complementary treat- China. Clin. Infect. Dis. 71, 762–768. 19 2020 be considered thoroughly, especially ment option for COVID- ? The question Quah, P., Li, A., and Phua, J. ( ). Mortality remains. Int. J. Antimicrob. Agents 56, rates of patients with COVID-19 in the inten- when toxicities affect organs injured in 106029. sive care unit: a systematic review of the thediseaseprocessofCOVID-19. Doi, K., Ikeda, M., Hayase, N., et al. (2020a). emerging literature. Crit. Care 24, 285. Nafamostat mesylate treatment in combina- Shi, Y., Wang, Y., Shao, C., et al. (2020). tion with favipiravir for patients critically ill COVID-19 infection: the perspectives on im- 19 24 27 Conclusions with Covid- : a case series. Crit. Care , mune responses. Cell Death Differ. , 392. 1451–1454. In summary, we have compiled litera- Doi, S., Akashi, Y.J., Takita, M., et al. (2020b). Su, H.-X., Yao, S., Zhao, W.-F., et al. (2020). ture of marketed drugs and supplements Preventing thrombosis in a COVID-19 patient Anti-SARS-CoV-2 activities in vitro of with preclinical and/or clinical data by combinatorial therapy with nafamostat and Shuanghuanglian preparations and bioactive 236 | Cicka and Sukhatme

ingredients. Acta Pharmacol. Sin. 41, Wan, W., Zhu, S., Li, S., et al. (2020). the recently emerged novel coronavirus 1167–1177. High-throughput screening of an FDA-approved (2019-nCoV) in vitro. Cell Res. 30, 269–271. Touret, F., Gilles, M., Barral, K., et al. (2020). In vi- drug library identifies inhibitors against arena- Wang, Y., Zhang, D., Du, G., et al. (2020c). tro screening of a FDA approved chemical li- viruses and SARS-CoV-2. ACS Infect. Dis. Remdesivir in adults with severe COVID-19:a brary reveals potential inhibitors of https://doi.org/10.1021/acsinfecdis.0c00486 randomised, double-blind, placebo-controlled, SARS-CoV-2 replication. Sci. Rep. 10, 13093. Wang, G., Yang, M.-L., Duan, Z.-L., et al. multicentre trial. Lancet 395, 1569–1578. Udwadia, Z.F., Singh, P., Barkate, H., et al. (2020a). Dalbavancin binds ACE2 to block Wiersinga, W.J., Rhodes, A., Cheng, A.C., et al. (2020). Efficacy and safety of favipiravir, an its interaction with SARS-CoV-2 spike protein (2020). Pathophysiology, transmission, diagno- oral RNA-dependent RNA polymerase inhibi- and is effective in inhibiting SARS-CoV-2 in- sis, and treatment of coronavirus Disease 2019 tor, in mild-to-moderate COVID-19: a random- fection in animal models. Cell Res. 31, (COVID-19): a review. JAMA 324, 782–793. ized, comparative, open-label, multicenter, 17–24. Ye, Z.-W., Yuan, S., Yuen, K.-S., et al. (2020). phase 3 clinical trial. Int. J. Infect. Dis. 103, Wang, M., Cao, R., Zhang, L., et al. (2020b). Zoonotic origins of human coronaviruses. Int. 62–71. Remdesivir and chloroquine effectively inhibit J. Biol. Sci. 16, 1686–1697. Downloaded from https://academic.oup.com/jmcb/article/13/3/232/6119634 by guest on 24 September 2021