COVID-19: The Potential Role of Copper and N-acetylcysteine (NAC) in a Combination of Candidate Antiviral Treatments Against SARS-CoV-2

Abstract

Background: On March 11, 2020, the World Health Organization (WHO) declared the outbreak of coronavirus disease (COVID-19) a pandemic. Since then, thousands of people have suffered and died, making the need for a treatment of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) more crucial than ever. Materials and Methods: The authors carried out a search in PubMed, Clinical Trials.gov and New England Journal of Medicine (NEJM) for COVID-19 to provide information on the most promising treatments against SARS-CoV-2. Results: Possible COVID-19 agents with promising efficacy and favorable safety profile were identified. The results support the combination of copper, N-acetylcysteine (NAC), colchicine and nitric oxide (NO) with candidate antiviral agents, remdesivir or EIDD-2801, as a treatment for patients positive for SARS-CoV-2. Conclusion: The authors propose to study the effects of the combination of copper, NAC, colchicine, NO and currently used experimental antiviral agents, remdesivir or EIDD-2801, as a potential treatment scheme for SARS-COV-2. Nowadays, the world is facing a pandemic of a newly discovered coronavirus disease, named COVID-19, with 4,037,574 confirmed cases and 279,236 deaths on May 10, 2020, worldwide (1). The most affected countries so far are: People's Republic of China, the United States of America (USA), Spain, Italy, Germany, France, Iran and the UK (1). CoVs are a group of enveloped viruses with a positive-sense single-stranded RNA genome that infect the pulmonary system, the intestines, the liver and the nerve cells of animals and humans (2). The taxonomy of these viruses includes the following genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus (3, 4). In each genus, several species that affect humans include: Human coronavirus 229E, Human coronavirus NL63, Betacoronavirus 1 (Human coronavirus OC43), Human coronavirus HKU1, Severe acute respiratory syndromerelated coronavirus (SARS-CoV, SARS-CoV-2), Middle East respiratory syndrome-related coronavirus (MERS-CoV) and Infectious bronchitis virus (3, 4). Infection with CoVs begins when an envelope glycoprotein, the viral spike (S) protein, which attaches to the host cells' angiotensin converting enzyme 2 (ACE2) receptor (5). This allows the virus to enter the host cell (5) by endocytosis or by direct fusion with the host cell membranes (6). This is considered as the main function of this glycoprotein (6), which assembles into trimers on the surface of the virus in order to form the "corona", the crown appearance of the virus (7). The protein is organized into two domains: a N-terminal S1 domain responsible for receptor binding and a C-terminal S2 domain responsible for viral fusion (7). The S protein consists of a furin site (polybasic cleavage site-RRAR) at the boundary of its two domains (8). This allows effective cleavage by furin and other 1567 This article is freely accessible online.

Rationale for the use of N ‐acetylcysteine in both prevention and adjuvant therapy of COVID‐19

“…A potential role of NAC and copper in combination with candidate antiviral treatments against SARS-CoV-2, such as remdesivir, has been hypothesized based on a systematic literature search. 71 Clearly, the potential anti-COVID-19 mechanisms and properties of this thiol have to be substantiated in controlled clinical trials, some of which are now in progress. 12,72…”

Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease

“…N -Acetylcysteine is a potential therapeutic in the treatment of COVID-19 ( Andreou et al, 2020 ). It is a mucolytic drug with antioxidant activity that is used in respiratory diseases ( Mokhtari et al, 2017 ) and skin diseases ( Adil et al, 2018 ), as well as an antidote in acetaminophen overdose ( Mokhtari et al, 2017 ).…”

“…In another meta-analysis study, N -acetylcysteine treatment of ARDS patients shortened their stay in the intensive care unit ( Zhang et al, 2017 ). Finally, it has also been suggested that N -acetylcysteine should be used in combination with other drugs to manage ARDS ( Guo et al, 2019 ; Andreou et al, 2020 ; Horowitz and Freeman, 2020 ). Currently, several clinical trials with N -acetylcysteine to treat COVID-19 (NCT04419025, NCT04455243, NCT04374461, etc.)…”

A Review on the Serum Electrolytes and Trace Elements Role in the Pathophysiology of COVID-19

“…So people who are using zinc supplements regularly may be at risk of severing SARS-CoV-2 because of malabsorption of Cu from jejunum [59]. Also, high intake of copper may have some adverse effects including gastrointestinal symptoms (cramps, abdominal pain, nausea, diarrhea, and vomiting) and kidney and liver toxicity resulting to coma [58].…”