Raman spectroscopy study of 7,8-dihydrofolate inhibition on the Wuhan strain SARS-CoV-2 binding to human ACE2 receptor.

Emerging evidence suggests that elevated levels of folic acid in the bloodstream may confer protection against Wuhan-SARS-CoV-2 infection and mitigate its associated symptoms. Notably, two comprehensive studies of COVID-19 patients in Israel and UK uncovered a remarkable trend, wherein individuals with heightened folic acid levels exhibited only mild symptoms and necessitated no ventilatory support. In parallel, research has underscored the potential connection between decreased folic acid levels and the severity of Covid-19 among hospitalized patients. Yet, the underlying mechanisms governing this intriguing inhibition remain elusive. In a quest to elucidate these mechanisms, we conducted a molecular dynamics simulation approach followed by a Raman spectroscopy study to delve into the intricate interplay between the folic acid metabolite, 7,8-dihydrofolate (DHF), and the angiotensin-converting enzyme ACE2 receptor, coupled with its interaction with the receptor-binding domain (RBD) of the Wuhan strain of SARS-CoV-2. Through a meticulous exploration, we scrutinized the transformation of the ACE2 + RBD complex, allowing these reactants to form bonds. This was juxtaposed with a similar investigation where ACE2 was initially permitted to react with DHF, followed by the exposure of the ACE2 + DHF complex to RBD. We find that DHF, when bonded to ACE2, functions as a physical barrier, effectively inhibiting the binding of the Wuhan strain RBD. This physicochemical process offers a cogent explanation for the observed inhibition of host cell infection in subjects receiving supplementary folic acid doses, as epidemiologically substantiated in multiple studies. This study not only sheds light on a potential avenue for mitigating SARS-CoV-2 infection but also underscores the crucial role of folic acid metabolites in host-virus interactions. This research paves the way for novel therapeutic strategies in the battle against COVID-19 and reinforces the significance of investigating the molecular mechanisms underlying the protective effects of folic acid in the context of viral infections.

The Folate Concentration and/or Folic Acid Metabolites in Plasma as Factor for COVID-19 Infection.

Pregnant women appear to be more susceptible to infectious diseases than women in reproductive age. According to the California Department of Public Health pregnant women were 9.6-folds more likely to be hospitalized during the 2009 influenza outbreak when compared to non-pregnant women in reproductive age. In contrast, it was reported that of 16,749 COVID-19 patients that were hospitalized in the UK, the probability for pregnant women to require in-patient care due to infection by SARS-CoV-2 was 0.95 versus non-pregnant women. Therefore 9.6/0.95 = 10.10, which brings us to the conclusion that pregnant women are 10.10-folds less likely to be hospitalized for a SARS-CoV-2 infection than for the 2009 H1N1 pandemic. Folic acid supplementation during pregnancy could be the factor that is protecting these patients against SARS-CoV-2 infection. Two independent papers that used informatic simulation proved that folic acid reduced the replication of this virus. One of them showed that folic acid inhibits the furin protease which the virus needs in order to enter its host cell, while the other one explained that folic acid inactivates protease 3CL pro , a protein that the virus needs to replicate. Nonetheless the probability that folic acid blocks two different proteins is very low, therefore the mechanism by which folic acid has apparently protected pregnant women during the COVID-19 pandemic has not been determined.