A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

Abstract

SARS-CoV-2 epidemics raises a considerable issue of public health at the planetary scale. T here is a pressing urgency to find treatments based upon currently available scientific knowledge. T herefore, we tentatively propose a hypothesis which hopefully might ultimately help saving lives. Based on the current scientific literature and on new epidemiological data which reveal that current smoking status appears to be a protective factor against the infection by SARS-CoV-2 [1], we hypothesize that the nicotinic acetylcholine receptor (nAChR) plays a key role in the pathophysiology of Covid-19 infection and might represent a target for the prevention and control of Covid-19 infection.

Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors

“…10 Based on the early observations of the lower than expected smoking prevalence in hospitalised COVID-19 patients, Changeux and colleagues suggested a role for nicotinic acetylcholine receptors (nAChRs) in the pathophysiology of COVID-19 via a direct interaction between these receptors and the viral spike (S) glycoprotein. 11 This suggestion was based in the fact that the S protein from SARS-CoV-2 contains a sequence motif similar to known nAChR antagonists 11 ( Figure S1), such as α-bungarotoxin from Bungarus multicinctus and glycoprotein from Rabies lyssavirus (formerly Rabies virus). Changeux et al also proposed that COVID-19 might be controlled or mitigated by the use of nicotine, if the latter can sterically or allosterically compete with the virus for binding to these receptors.…”

“…Changeux et al also proposed that COVID-19 might be controlled or mitigated by the use of nicotine, if the latter can sterically or allosterically compete with the virus for binding to these receptors. 9,11 nAChRs are cation channels that belong to the pentameric ligand-gated ion channel family. 12 They are present in both the peripheral (at the skeletal neuromuscular junction and in the autonomic nervous system) and central nervous system (CNS).…”

“…The Y674-R685 region contains the 4-residue PRRA insertion not present in other SARS-CoV-related coronaviruses, 24 and includes a sequence motif homologous to several neurotoxins known to target nAChRs. 11 In SARS-CoV-2, abrogation of the PRRA motif moderately affects virus entry into cells. 21,22 This motif has recently been shown experimentally to interact with neuropilin-1 receptors 25 and has also been suggested to have an affinity for T cell receptors.…”

Beyond Smoking Cessation: Investigating Medicinal Nicotine to Prevent and Treat COVID-19

“…In the absence of treatment or a vaccine, the SARS-CoV-2 pandemic challenges the medical community to identify novel containment strategies. Changeux et al 1 have proposed the nicotinic hypothesisthat nicotinic acetylcholine receptors may be a therapeutic target to reduce SARS-CoV-2 infection and mitigate COVID-19 disease. Testing the nicotinic hypothesis has implications to prevent and treat COVID-19 disease among billions of patients and health care providers, including those who smoke cigarettes and those who do not.…”

“…French researchers recently announced plans for a randomized controlled trial to test medicinal nicotine to prevent and treat COVID-19 in providers and patients with moderate and severe illness. 1 Similar US studies would likely be needed to obtain Food and Drug Administration approval for this indication. A complementary approach could leverage data from existing National Institutes of Health-sponsored randomized controlled trials in nonsmokers, such as an ongoing trial testing whether medicinal nicotine improves symptoms in older adults with mild cognitive impairment.…”