OTC Drug Diphenhydramine Paired With Lactoferrin Could Be A New Therapeutic For COVID-19


A new study by scientists from the University of Florida-USA and the University of Saskatchewan has found that the common over-the-counter antihistamine diphenhydramine when paired with the commonly available supplement lactoferrin, a protein found in cow and human milk, the pair had the capability to hinder the SARS-CoV-2 virus during tests in monkey cells and human lung cells.

The experiments showed encouraging results even with various types of SARS-CoV-2 variants used, paving the path for further human clinical trials of using the pair as COVID-19 therapeutics and even as prophylactics.
As the SARS-CoV-2 coronavirus and its emerging variants and sub-variants continues to ravage the world, there is a strong need for prevention and treatment strategies for COVID-19 that are not impacted by SARS-CoV-2 mutations emerging in variants of concern.
It has been found that after virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex.
The COVID-19 Drugs study team investigated highly specific sigma receptor ligands for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity.
The study findings showed that antiviral activity associated with agonism of the sigma-1 receptor (e.g., SA4503), ligation of the sigma-2 receptor (e.g., CM398), and a combination of the two pathways (e.g., AZ66).  Intermolecular contacts between these ligands and sigma receptors were identified by structural modeling.
The study findings showed that sigma receptor ligands and drug or supplements such as diphenhydramine and lactoferrin with off-target sigma receptor binding characteristics were effective at inhibiting SARS-CoV-2 infection in primate and human cells, representing a potential therapeutic avenue for COVID-19 prevention and treatment.
The study findings were published in the peer reviewed journal: Pathogens. 


There is a strong need for safe drugs and vaccines to target emerging pathogens such as SARS-CoV-2. Although recent studies identified approved drugs that exhibit antiviral activities against SARS-CoV-2 [1,2], current therapeutic treatment strategies for COVID-19 have limited effectiveness.

There are currently no oral medications given emergency use authorization from the Food and Drug Administration to prevent SARS-CoV-2 infection or to treat COVID-19.

There is an urgent need to identify safe, economical, orally deliverable approved drugs with activity against SARS-CoV-2 to prevent infection in at-risk populations, and to treat patients experiencing viral disease [3]. Attempts to identify approved drugs with antiviral activity led to the discovery of more than 100 compounds that exhibit direct antiviral activity against SARS-CoV-2 isolates in vitro [2,4,5,6].

Although the on- and off-target binding mechanisms that mediate anti-SARS-CoV-2 activity are not clear, two classes of molecules were previously found to effectively inhibit virus infectivity: protein biogenesis inhibitors (e.g., zotatifin, ternatin-4, PS3061) and ligands of the sigma-1 and sigma-2 receptors (e.g., haloperidol, clemastine, cloperastine) [7].

Specific antihistamines with off-target antiviral activity may have repurposed utility for prevention and treatment of COVID-19 because of known safety profiles and widespread availability. Common antihistamines that exhibit off-target antiviral activity include hydroxyzine, azelastine and diphenhydramine [8].

Mechanisms of action for drugs with direct anti-SARS-CoV-2 activity have important clinical implications in terms of dosing and drug interactions. Defining mechanisms that drive antiviral activity against SARS-CoV-2 will provide rationale for drug combinations targeting distinct antiviral pathways [9].

Drug combinations that target separate antiviral pathways are expected to inhibit drug resistant variants resulting from emerging mutations.

Coronaviruses replicate in a modified compartment derived from the endoplasmic reticulum (ER). The sigma receptor-1 is an ER resident chaperone that normally functions to modulate the ER stress response [10]. Coronavirus infection activates pathways to facilitate adaptation of ER stress to virus proliferation. These pathways are thought to hijack the host cell ER stress response to modulate protein translation, ER protein folding capacity and ER-associated degradation. Targeting the ER stress response could elucidate coronavirus protein-host interactions and provide rationale for new therapeutic approaches to prevention and treatment of COVID-19.

In infected cells, the sigma-1 receptor was shown to link the SARS-CoV-2 replicase/transcriptase complex to the ER membrane by binding directly to nonstructural protein 6 (NSP6) [7]. Although sigma-1 receptor ligands exert antiviral activity against non-coronaviruses and coronaviruses [10], it is not known if agonist or antagonist activities prevent SARS-CoV-2 infection. Understanding binding interactions of antiviral sigma-1 receptor ligands may provide the basis for drug development and optimization.

Although approved drugs that inhibit SARS-CoV-2 in vitro have been shown to bind sigma-2 receptors, the structure and functions of sigma-2 receptors are not well characterized or understood [11]. Sigma-1 and sigma-2 receptors are unrelated in sequence and structure. The sigma-2 receptor is an ER resident membrane protein thought to be involved in hormone, calcium and neuronal signaling [12].

The sigma-2 receptor regulates cholesterol transport and contributes to cholesterol homeostasis [13]. In infected cells, the sigma-2 receptor was shown to bind directly to SARS-CoV-2 ORF9c [7], suggesting that sigma-2 receptor ligands may block host protein:virus protein interactions. Recently, the sigma-1 and -2 ligand PB28 that had sub-nanomolar in vitro SARS-CoV-2 inhibitory effects was found ineffective in vivo (33). The hypothesized cause for poor efficacy was that this compound induced high levels of phospholipidosis in vitro that resulted in virus inhibition that could not be achieved in vivo.

Sigma receptor ligands, as a class, should not be discounted because of the poor performance of a single compound. In this work, we demonstrate phospholipidosis induction by sigma ligands does not correlate with inhibition of SARS-CoV-2 viral replication.

It is clear that multiple sigma receptor ligands exhibit antiviral properties against SARS-CoV-2, but the relative roles of the sigma-1 receptor and sigma-2 receptor agonism and antagonism in modulating antiviral activities are not known. In this study, antiviral activities of highly selective ligands (Figure 1) were measured to define mechanisms driving inhibition of SARS-CoV-2 infection in vitro: a sigma-1 receptor specific agonist (SA4503, cutamesine) [14,15,16], sigma-1 receptor antagonist (CM304) [17], sigma-2 receptor specific ligand (CM398) [18], and a mixed affinity sigma-1/sigma-2 ligand (AZ66) [19,20].

The benzothiazolone (CM304 and AZ66) and benzimidazolone (CM398) containing compounds were selected for their demonstrated selectivity for sigma receptors against other aminergic transporters or receptors [21]. In addition, the specific compounds were chosen for their differential affinity at the two receptor subtypes, aiming to clarify the involvement of each receptor in the inhibition of SARS-CoV-2 infection in vitro.

Pathogens 10 01514 g001
Figure 1. Structures of sigma ligands utilized in this and other studies. The structure of sigma ligands important to this study are presented with the sigma specific activity, Ki for the respective sigma receptor binding property, and the bioavailability if known. (A) SA4503 (cutamesine) is a selective Sigma-1 piperazine agonist with > 15-fold preference for sigma-1 over sigma-2. (B) CM304 is a highly selective benzothiazolone sigma-1 antagonist. (C) CM398 is a highly selective benzimidazolone-based sigma-2 ligand. (D) AZ66 is a mixed sigma-1/sigma-2 selective ligand with an optimized pharmacokinetic profile. (E) PB28 is not utilized in this study but recent work demonstrated its utility in vitro was compromised by its toxicity and is included as a structural comparison to the other compounds tested in this work.


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