Abstract
The COVID-19 pandemic has highlighted an important role for drug repurposing. Quaternary ammonium compounds such as ammonium chloride, cetylpyridinium and miramistin represent widely accessible antiseptic molecules with well-known broad-spectrum antiviral activities and represent a repurposing opportunity as therapeutics against SARS-CoV-2.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
The coronavirus family recently gained a new member in SARS-CoV-2 to go along with SARS-CoV and MERS-CoV. Infection with SARS-CoV-2 causes COVID-19 which has rapidly become a pandemic (with at the time of writing millions infected and hundreds of thousands dead) requiring social distancing, leading to global shutdowns, resulting in a recession, and pushing healthcare infrastructures to the breaking point. This pandemic is demanding an urgent response and we need to rapidly find treatments which can be accomplished by using existing drugs. Thus, drug repurposing for COVID-19 has garnered mainstream attention which did not occur in previous epidemics (1).
Initially the response from China and elsewhere was for scientists to look at compounds tested previously against SARS and MERS almost exclusively (2). Ritonavir/lopinavir, remdesivir (repurposed from Ebola and FDA emergency approved), chloroquine and hydroxychloroquine (both now FDA emergency approved, see Supplementary Material) are the most well-known compounds currently in clinical trials. Other drug repurposing efforts have used computational approaches such as docking or biological network mining to identify molecules as candidates for future testing (2,3,4,1). Limitations of the text mining approach are that at the time of writing there had only been reports of approximately 450 molecules associated with other coronaviruses and many of these could likely be discounted due to no reported antiviral activity, toxicity and perhaps most important, the lack of FDA approved status.
Summary
We propose that in particular, cetylpyridinium chloride is a simple molecule that is cheap, safe, clinically approved, widely accessible in hospitals and the consumer sector and which could enter clinical trials immediately. If reported to have activity in vitro against SARS-CoV-2 subsequent delivery in the form of a mouthwash or nasal spray containing this compound may be an effective way both to combat the virus at its point of entry and reduce SARS-CoV-2 transmission. Similarly, this compound could be added to shampoo and body cleansers so that one could effectively bathe in low concentrations of this compound to destroy shed coronavirus. Cetylpyridinium chloride and many other quaternary ammonium compounds have already demonstrated their antiviral activity against a wide array of related coronaviruses as disinfectants and antiseptics, therefore they represent especially low hanging fruit for testing in humans. Due to their reported mechanisms they may also have much broader activity against viruses which could be useful to address future enveloped viruses. Certainly, additional studies may be warranted to assess potential drug-drug or drug-transporter interactions. This work may also point to other related compounds that could be utilized, or at least enable the generation of new antiviral compounds that leverage the quaternary ammonium substructural fragment as a potential warhead. As simple as it sounds, it is entirely possible that we should be looking in our bathroom cupboards, for potential remedies against COVID-19.
References
Gates B. Responding to Covid-19 - a once-in-a-century pandemic? N Engl J Med. 2020;382:1677–9.
Ekins S, Mottin M, Ramos PRPS, Sousa BKP, Neves BJ, Foil DH, Zorn KM, Braga RC, Coffee M, Southan C, Puhl AC, Andrade CH. Déjà vu: Stimulating Open Drug Discovery for SARS-CoV-2. Drug Discov Today. 2020; Apr 19:S1359-6446(20)30145-8. https://doi.org/10.1016/j.drudis.2020.03.019.
Stebbing J, Phelan A, Griffin I, Tucker C, Oechsle O, Smith D, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020;20(4):400–2.
Jeon S, Ko M, Lee J, Choi I, Byun SY, Park S, Shum D, Kim S. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Available from: https://www.biorxiv.org/content/10.1101/2020.03.20.999730v1.
** Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L, Peng C, Duan Y, Yu J, Wang L, Yang K, liu F, Jiang R, Yang X, You T, Liu X, Yang X, Bai F, Liu H, Liu X, Guddat LW, Xu W, **ao G, Qin C, Shi Z, Jiang HY, Rao Z, yang H. Structure of Mpro from 1 COVID-19 virus and discovery of its inhibitors. Available from: https://www.biorxiv.org/content/10.1101/2020.02.26.964882v2.
Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269–71.
Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Burgstaller-Muehlbacher S, Pache L, De Jesus PP, Hull MV, Chang M, Chan JF-W, Cao J, Poon VK-M, Herbert K, Nguyen T-T, Pu Y, Nguyen C, Rubanov A, Martinez-Sobrido L, Liu W-C, Miorin L, White KM, Johnson JR, Benner C, Sun R, Schultz PG, Su A, Garcia-Sastre A, Chatterjee AK, Yuen K-Y, Chanda SK. A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals. bioRxiv. 2020:2020.2004.2016.044016.
de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58(8):4875–84.
Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J, et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014;58(8):4885–93.
Baker NC, Ekins S, Williams AJ, Tropsha A. A bibliometric review of drug repurposing. Drug Discov Today. 2018;23(3):661–72.
Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, Mourao MPG, Brito-Sousa JD, Baia-da-Silva D, Guerra MVF, Hajjar LA, Pinto RC, Balieiro AAS, Pacheco AGF, Santos JDO, Jr., Naveca FG, Xavier MS, Siqueira AM, Schwarzbold A, Croda J, Nogueira ML, Romero GAS, Bassat Q, Fontes CJ, Albuquerque BC, Daniel-Ribeiro CT, Monteiro WM, Lacerda MVG, CloroCovid T. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open. 2020;3(4):e208857.
Mizzen L, Hilton A, Cheley S, Anderson R. Attenuation of murine coronavirus infection by ammonium chloride. Virology. 1985;142(2):378–88.
Hoffmann MM, Kleine-Weber H, Kruger N, Muller M, Drosten C, Pohlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor 2 ACE2 and the cellular protease TMPRSS2 for entry into target cells. Available from: https://www.biorxiv.org/content/10.1101/2020.01.31.929042v1.full.pdf.
Ashfaq UA, Javed T, Rehman S, Nawaz Z, Riazuddin S. Lysosomotropic agents as HCV entry inhibitors. Virol J. 2011;8:163.
Rabenau HF, Kampf G, Cinatl J, Doerr HW. Efficacy of various disinfectants against SARS coronavirus. J Hosp Infect. 2005;61(2):107–11.
Dellanno C, Vega Q, Boesenberg D. The antiviral action of common household disinfectants and antiseptics against murine hepatitis virus, a potential surrogate for SARS coronavirus. Am J Infect Control. 2009;37(8):649–52.
Anon. Disinfectant Concentrations and Contact Times for EPA's List of Products Effective against Novel Coronavirus SARS-CoV-2, the Cause of COVID-19. 2020 1 April. Available from: https://www.ecri.org/components/HDJournal/Pages/Disinfectant-Concentrations-for-EPA-list-N-COVID-19.aspx?tab=2.
Zhu DM, Evans RK. Molecular mechanism and thermodynamics study of plasmid DNA and cationic surfactants interactions. Langmuir. 2006;22(8):3735–43.
Fromm-Dornieden C, Rembe JD, Schafer N, Bohm J, Stuermer EK. Cetylpyridinium chloride and miramistin as antiseptic substances in chronic wound management - prospects and limitations. J Med Microbiol. 2015;64(Pt 4):407–14.
Mukherjee PK, Esper F, Buchheit K, Arters K, Adkins I, Ghannoum MA, et al. Randomized, double-blind, placebo-controlled clinical trial to assess the safety and effectiveness of a novel dual-action oral topical formulation against upper respiratory infections. BMC Infect Dis. 2017;17(1):74.
Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci U S A. 2005;102(33):11876–81.
Krivorutchenko Iu L. KrivosheinIuS, Marennikova SS, Stepanova LG, Nosik DN, Kalnina LB, Rud'ko AP. [study of the anti-HIV activity of miramistin]. Vopr Virusol. 1994;39(6):267–9.
Agafonov AP, Skarnovich MO, Petrishchenko VA, Shishkina LN, Sergeev AN, Svistov VV, et al. In vitro study of antiviral activity of Myramistin against subtypes H3N2 and H5N1 of influenza virus. Antibiot Khimioter. 2005;50(12):9–11.
ACKNOWLEDGMENTS AND DISCLOSURES
This work has been reviewed at the US EPA and has been approved for publication. The views expressed in this publication are those of the authors and do not necessarily represent the views or policies of the United States Environment Protection Agency. Reference to commercial products or services does not constitute endorsement.
Funding
We kindly acknowledge NIH funding: R44GM122196-02A1 from NIGMS, R21TR001718 from NCATS and R43AT010585-01S1 from NCCAM (PI – Sean Ekins) and 1OT2TR002514–01 (Pi – Alexander Tropsha).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
SE is CEO and owner of Collaborations Pharmaceuticals. All other co-authors have no conflicts of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 47 kb)
Rights and permissions
About this article
Cite this article
Baker, N., Williams, A.J., Tropsha, A. et al. Repurposing Quaternary Ammonium Compounds as Potential Treatments for COVID-19. Pharm Res 37, 104 (2020). https://doi.org/10.1007/s11095-020-02842-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11095-020-02842-8