








key: cord-338585-ep9r1n8t
authors: Perrin, David M.
title: A hypothesis for examining dihydroxyacetone, the active component in self-tanning products, as a topical prophylactic against SARS-COV-2 transmission
date: 2020-09-16
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.110280
sha: 
doc_id: 338585
cord_uid: ep9r1n8t

This hypothesis raises the interesting prospect that dihydroxyacetone (DHA), the key ingredient in self-tanning creams, when applied daily to the face and hands may have prophylactic action against SARS-COV-2 transmission and infection. The scientific and mechanistic basis for this hypothesis is elaborated based on our understanding of the chemical reactivity of DHA with proteins to afford advanced glycation products. This piece ends with a proposal for doing key experiments that can be run to test this hypothesis. As more than 20 million people have been infected with this disease world-wide, a safe method for stopping spread is worthy of consideration. Publication of this hypothesis would enable the scientific community at large to test this in a clinically meaningful setting to address the potential for DHA-based prophylaxis. Given the calamity of this crisis, it is anticipated that the publication of this hypothesis, which is supported by key studies on protein and nucleoside glycation, can be disseminated to as many researchers as possible.

David M. Perrin, Ph.D., Chemistry Department, 2036 Main Mall -UBC, Vancouver, BC, V6T1Z1, dperrin@chem.ubc.ca

As SARS-COV-2 ravages the world, over 28 million people and counting have now tested positive for the disease while mortality rates are of great concern. The virus is transmitted by: 1) respiration of aerosolized droplets containing the virus; 2) contaminated hands passing the virus directly into the eyes or mouth; and 3) transferring the virus that lands on the face to the eyes, nose, or mouth by face touching. As the hands and face is known to be a major point of transmission, there has been an urgent need to identify safe chemicals that could be applied topically to the skin to reduce the risk of facial transmission. Dihydroxyacetone (DHA, Figure 1 ), the active ingredient in sunless tanning creams, which gives a characteristic orange color, may be of significant and immediate interest.

DHA reacts chemically with proteins to form glycation products and thus would be expected to react analogously with viral components such that it might provide prophylactic action against anti-SARS-CoV-2. If so, this cheap, nontoxic molecule may be worthy of consideration for limiting facial transmission, notwithstanding the cosmetic value. Here, I will review the paraclinical history of DHA and provide sound biochemical evidence of its chemical reactivity towards either protein e.g. the viral coat and nucleocapsid proteins, or RNA e.g. the viral genome to support measured exploration of its topical use to prevent facial transmission.

Dihydroxyacetone is the simplest keto-sugar and its monophosphate ester (dihydroxyacetone phosphate -DHAP) is an intermediate in glycolysis. Nearly a century ago, DHA was first administered orally in a failed attempt to treat type-I diabetic children with a "keto" diet(1, 2) designed to bypass glycolysis. While ineffective for treating diabetes, DHA was found to be nontoxic. Nevertheless, this treatment resulted in apparent superficial discoloration in the gums and mouth(3) while regurgitation of DHA on the skin resulted in notable discoloration that led to the serendipitous discovery that DHA could be used for sunless tanning. Subsequently, DHA was investigated for topical applications to treat vitiligo(4). Considered to be safe, DHA is now used as the key ingredient in sunless tanning products that are widely available without prescription(5, ). While such products may be used with varied frequency, the more frequent the use, the greater the effect, with twice-daily use providing maximal effect (7) often marked by a distinctive orange hue.

DHA's action is limited to the outer dermal layer of the stratum corneum where it colors dead skin cells. There, it condenses dehydratively with the amine and guanidine nucleophiles of lysine and arginine found in keratin and other proteins(8-10) via the famous Maillard Reaction(11) (or browning reaction) to afford chromophores accounting for the characteristic pumpkin color. The Maillard Reaction, comprises a manifold of reactions including Schiff-base formation, aldol-type condensations, Amadori rearrangements, and dehydrative and/or oxidative aromatization events that modify lysine amines and give rise to crosslinks, (12) which are consistent with other advanced glycation events seen in diabetic patients.

A recent report characterized certain products of this cascade in the context of several reducing sugars, most notably DHA (10) , which led to several substituted lysine-modified pyridinium salts, exemplified by compound 5a, Figure 2 (and detailed therein for those who might not be familiar with this process), which is further capable of crosslinking the nitrogen atoms of lysine and arginine. Figure 2 : Maillard reaction of "3-carbon" sugars with lysine to give glycation products 5a-c by a series of reactions including aldol, Amadori rearrangements and oxidation events. Compound 5b is one of several conceivable adducts to arginine resulting from oxidation. The formation of 5c, currently unknown, is proposed here as an alternative product resulting from a Hantzsch-type pyrrole synthesis.

The formation of 5a and related congeners has been extensively characterized by HRMS analysis as well as by 1 H-and 13 C-NMR, and UV-vis spectroscopy, based on the reaction of various three-carbon sugars with lysine. As these aromatic Amadori products are capable of acting as photosensitizers that generate free radicals (13) , the formation of heterocycles e.g. 5c, which might serve as important reductants in radical processes that may contribute to a much more extensive array of chemical reactions.

Besides the chromogenic reaction that occurs between DHA and proteins, DHA has also been found to glycate the nucleic acids: under in vitro conditions, reducing sugars are known to glycate the exocyclic amines of nucleosides, in particular guanine, as seen for DNA (14) (15) (16) preventing infectivity of bacteriophages. In addition, there is evidence that reducing sugars including fructose (a related keto sugar) rapidly crosslink lysine to DNA (17) in vitro.

While the evidence for amino-acid (protein) glycation at ambient pH is much stronger than that for nucleoside modification, the potential relevance to SARS-COV-2 topical prophylaxis becomes apparent. As the outer dermal lay of skin is expected to be much more dehydrating that the aqueous conditions that are generally used to assay glycation in vitro, it reasonable to suspect that DHA may be capable of modifying one or more of the 61 lysines and/or 48 arginines on the spike protein (Genebank QHD43416.1), which interacts with ACE2 receptor enabling viral entry. Additionally, the N-terminal domain of the nucleocapsid protein, with 7 lysines and 5 arginines, which provide electrostatic complementarity to the polyanionic RNA genome, may also be a target for glycation, does the RNA genome itself, which might undergo crosslinking to the nucleocapsid protein.

Given the need to stanch viral transmission, it would be especially attractive to identify a molecule that is cheap, safe, FDA-approved, and already found in commercial formulations for topical application. DHA necessarily meets all of these characteristics. Taken together, a solid body of scientific evidence provides a reasonable chemical basis to support the hypothesis that DHA may dehydratively glycate viral proteins and/or viral genomic RNA, which would in turn be expected to inactivate the virus, thus prophylactically protecting the wearer from facial transmission. Finally, independent support for DHA application is found in an isolated report that describes the antifungal activity of DHA to treat dermatomycosis(18) further highlighting potential biocidal activity.

In the absence of a clinical study, I can only provide sound biochemical evidence to support this hypothesis to highlight the chemical rationale for exploring the potential of studying whether DHA could protect against SARS-COV-2 transition. Herein, several studies are proposed. To start, studies could be undertaken to score viral transfectivity following application of live virus to non-living surfaces (19) that have been coated with DHA compared to those that have not. It may be possible to explore a human trial, which would involve little concern for side effects. For example, in assisted living facilities where there is the highest risk to life, residents could be asked to apply a commercially available DHA-containing cream to face and hands. Likewise, health workers, who are typically at higher risk of exposure, could volunteer to apply self-tanning cream to hands and face on semi-daily basis. Incidence of infection could then be scored in relation to the DHA application or lack thereof. Together, such studies would systematically advance this hypothesis from well-established in vitro results to an easily monitored clinical trial, that would lead to a medically justified recommendation for daily topical prophylactic application of DHA to the face and hands for reducing SARS-COV-2 infection.

As a chemist, I have based this proposal on sound biochemical logic and wellestablished in vitro evidence of DHA-based glycation with citations of peer-reviewed scientific publications. With limited funding and no access to viral strains in my own lab, I submit this Hypothesis in the hope that it will inspire medical researchers who are equipped with the proper biosafety containment level-3 and clinicians who are certified to treat high-risk individuals in clinical settings/care facilities to consider the proposed experiments.

In no way do I advocate ingestion of DHA. Nor do I advocate use of self-tanning products as a prophylactic until these experiments are properly conducted. Furthermore, in no way do I suggest DHA applications should obviate wearing a mask, social distancing or hand washing.

The influence of dihydroxyacetone upon the blood sugar and glycosuria

Investigative studies with the skin coloring agents dihydroxyacetone and glyoxal -preliminary report

Staining of Skin with Dihydroxyacetone

Dihydroxyacetone in a New formulation -A powerful therapeutic option in vitiligo

Dihydroxyacetone and sunless tanning: Knowledge, myths, and current understanding

Dihydroxyacetone: An Updated Insight into an Important Bioproduct

Dihydroxyacetone -A Suntan Simulating Agent

Dihydroxyacetone (DHA) -A Keratin Coloring Agent

Reaction of Dihydroxyacetone (DHA) with Human Skin Callus and Amino Compounds

Triosidines: novel Maillard reaction products and cross-links from the reaction of triose sugars with lysine and arginine residues

A synthesis of humic matter by effect of amine acids on sugar reducing agents

Pyridinium-carbaldehyde: active Maillard reaction product from the reaction of hexoses with lysine residues

3-hydroxypyridine chromophores are endogenous sensitizers of photooxidative stress in human skin cells

Modificaiton of DNA by Reducing Sugars -A possible mechanism for nucleic acid aging and age-related dysfunction in geneexpression

Modification of DNA by Glucose-6-phosphate Induces DNA Rearrangements in an Escherichia-coli Plasmide

Reaction of guanosine with glucose under oxidative conditions

The formaiton of reactive intermediate(s) of gluocose-6-phosphate and lysine capable of rapidly reacting with DNA

Vitro Antifungal Activity of Dihydroxyacetone Against Causative Agents of Dermatomycosis

Stability of human metapneumovirus and human coronavirus NL63 on medical instruments and in the patient environment

I attest that I have no conflicts in submitting this work.

