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What the latest studies say

No vaccine or drug has been approved to date 

Monoclonal antibodies represent the main class of biotherapy for passive immunotherapy to combat viral infections (1). However, they have contraindications that need to be assessed on a case-by-case basis.

A temporary suggestion, probably resistant to new coronavirus mutations, is the use of angiotensin type 1 receptor blockers as a therapy to reduce aggressiveness and mortality from SARS-CoV-2 virus infections (2).

Approved nucleoside analogues marketed and approved in Japan under the name Avigan®, as well as ribavirin (Tribavirin or Virazole) and experimental nucleoside analogues such as remdesivir (a nucleotide-like formula currently under clinical trial for the treatment of Ebola virus infections) and galidesivir,  may have potential on 2019-nCoV (3) but remdesivir appeared superior in efficacy to lopinavir/ritonavir and interferon beta versus MERS-CoV in a model of humanized transgenic mice (4).  Regarding efficacy, favipiravir demonstrated an IC50 (concentration required to inhibit 50% of the target) of 601 μM versus 3.9 μM of ribavirin (5), but its use is approved with limitations as it has a risk of teratogenicity and embotoxicity (6).

This study provides the first generation of MERS-CoV fusion inhibitors with potencies in the low micromolar range (7).

Chloroquine phosphate, an already effective drug for the treatment of malaria, has been shown to have an apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicentre clinical trials conducted in China (8) tablet, 500mg twice per day for 10 days for patients diagnosed as mild, moderate and severe cases of novel coronavirus pneumonia and without contraindications to chloroquine (9) and already proposed 20 years ago by the authors of this study as effective in vitro against a wide range of viruses (10), another study also considers Hydroxychloroquine more potent and more tolerable (11).

Procalcitonin  prohormone precursor of calcitonin, a diagnostic biomarker approved by the FDA in 2005, for patients with more severe symptoms of Coronavirus 2019 (COVID-19) (12) in intensive care unit (ICU).

In in vitro experiments were found to be effective against pangolin-borne coronavirus, cepharanthin alkaloid, selamectin, and mefloquine hydrochloride, a known malaria remedy (13).

People in old age are more likely to contract acute respiratory distress syndrome (ARDS) and this study suggests treatment with methylprednisolone (14), synthetic glucocorticoid and powerful anti-inflammatory.

Highly Standardized Mixture of Active Compounds Derived From Cultured Lentinula Edodes Mycelia (AHCC) action in promoting a protective response to a wide range of viral infections, and the current absence of effective vaccines, could support its use in the prevention of diseases provoked by human pathogenic coronavirus, including COVID-19 (15). 

It is important to understand the defense dynamics of coronavirus to try to inhibit its replication, a very complex process aimed at preserving its large RNA genome. Replication and maturation of the virus have essential strengths in several proteases including Mpro or 3CL and papain-like protease (PLpro) both capable of generating mature proteins. 

In previous MERS-CoV and SARS-CoV, disufiram (Tetraethylthiuram disulfide, Antabuse™) had been shown to inhibit papain protease and act as an allosteric inhibitor for MERS-CoV and as a competitive (or mixed) SARS-CoV inhibitor (16). It should not be co-administered with lopinavir/ritonavir (17).

In fact, PLpro plays a fundamental role in the defense of the virus as first of all it has the task of shaking off the proteins of the host cells that try, with the immune response, to neutralize the virus (18) and also plays a pharmacokinetic interaction on the stimulation of the host interferon through its deubiquitination activity (19).

Disulfiram is a well-known remedy against alcoholism, but has also recently demonstrated its effectiveness against cancer, leukemia and, importantly, a low toxicity (20). This study showed that the disulfiram/copper complex significantly induced the arrest of the cell cycle in the G2/M phase in MM.1S and RPMI8226 cells (21).

Between 2005 and 2009 some studies identified 6-mercaptopurine (anticancer drug approved  by the US Food and Drug Administration (FDA) ), 6-thioguanine (a chemotherapeutic drug) and mycophenolic acid as compounds capable of inhibiting MERS-CoV PLpro by their synergistic effects and providing a basis for antiviral drugs (22) (23)

In 2018, during the PEDV pig epidemic, 6-thioguanine was suggested as a non-competitive PLpro inhibitor (24).

Another anti-malarial anti-infective drug, mefloquine, structurally related to quinine, which is often combined with artesunate (a semi-synthetic derivative of artemisininin) could provide results in the fight against coronavirus, but has contraindications for both long term treatment and potential side effects (25).

References_________________________________________________________

((1) Shanmugaraj B, Siriwattananon K, Wangkanont K, Phoolcharoen W.Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19).    Asian Pac J Allergy Immunol. 2020 Mar 4. doi: 10.12932/AP-200220-0773.

(2) Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.  Drug Dev Res. 2020 Mar 4. doi: 10.1002/ddr.21656.

(3) Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV).   Nat Rev Drug Discov. 2020 Mar;19(3):149-150. doi: 10.1038/d41573-020-00016-0.               

Dong L, Hu S, Gao J.  Discovering drugs to treat coronavirus disease 2019 (COVID-19).   Drug Discov Ther. 2020;14(1):58-60. doi: 10.5582/ddt.2020.01012.

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(5) Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL.  Favipiravir (T-705), a novel viral RNA polymerase inhibitor.  Antiviral Res. 2013 Nov;100(2):446-54. doi: 10.1016/j.antiviral.2013.09.015.

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(7) Kandeel M, Yamamoto M, Al-Taher A, Watanabe A, Oh-Hashi K, Park BK, Kwon HJ, Inoue JI, Al-Nazawi M.  Small Molecule Inhibitors of Middle East Respiratory Syndrome Coronavirus Fusion by Targeting Cavities on Heptad Repeat Trimers.   Biomol Ther (Seoul). 2020 Mar 4. doi: 10.4062/biomolther.2019.202.

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(12) Lippi G, Plebani M.   Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis.   Clin Chim Acta. 2020 Mar 4. pii: S0009-8981(20)30106-6. doi: 10.1016/j.cca.2020.03.004.

Chanu Rhee, Using Procalcitonin to Guide Antibiotic Therapy, Open Forum Infectious Diseases, Volume 4, Issue 1, Winter 2017, ofw249, https://doi.org/10.1093/ofid/ofw249

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(15) Di Pierro F, Bertuccioli A, Cavecchia I. Possible therapeutic role of a highly standardized mixture of active compounds derived from cultured Lentinula edodes mycelia (AHCC) in patients infected with 2019 novel coronavirus [published online ahead of print, 2020 Mar 12]. Minerva Gastroenterol Dietol. 2020;10.23736/S1121-421X.20.02697-5. doi:10.23736/S1121-421X.20.02697-5

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(17) Cvetkovic RS, Goa KL. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003;63(8):769–802. doi:10.2165/00003495-200363080-00004

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(19) Báez-Santos YM, St John SE, Mesecar AD. The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral Res. 2015 Mar;115:21-38. doi: 10.1016/j.antiviral.2014.12.015. 

(20) Sheppard JG, Frazier KR, Saralkar P, Hossain MF, Geldenhuys WJ, Long TE. Disulfiram-based disulfides as narrow-spectrum antibacterial agents. Bioorg Med Chem Lett. 2018;28(8):1298–1302. doi:10.1016/j.bmcl.2018.03.023

(21) Xu Y, Zhou Q, Feng X, et al. Disulfiram/copper markedly induced myeloma cell apoptosis through activation of JNK and intrinsic and extrinsic apoptosis pathways [published online ahead of print, 2020 Mar 4]. Biomed Pharmacother. 2020;126:110048. doi:10.1016/j.biopha.2020.110048

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(25) Nevin RL, Byrd AM. Neuropsychiatric Adverse Reactions to Mefloquine: a Systematic Comparison of Prescribing and Patient Safety Guidance in the US, UK, Ireland, Australia, New Zealand, and Canada. Neurol Ther. 2016;5(1):69–83. doi:10.1007/s40120-016-0045-5