Diphenhydramine for COVID-19

(1) Background: 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. After virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex. (2) Methods: In this work, highly specific sigma receptor ligands were investigated for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity. This study found 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). (3) Results: Intermolecular contacts between these ligands and sigma receptors were identified by structural modeling. (4) Conclusions: Sigma receptor ligands and drugs 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.

Abstract Background Many respiratory viruses attack the airway epithelium and cause a wide spectrum of diseases for which we have limited therapies. To date, a few primary human stem cell-based models of the proximal airway have been reported for drug discovery but scaling them up to a higher throughput platform remains a significant challenge. As a result, most of the drug screening assays for respiratory viruses are performed on commercial cell line-based 2D cultures that provide limited translational ability. Methods We optimized a primary human stem cell-based mucociliary airway epithelium model of SARS-CoV-2 infection, in 96-well air–liquid-interface (ALI) format, which is amenable to moderate throughput drug screening. We tested the model against SARS-CoV-2 parental strain (Wuhan) and variants Beta, Delta, and Omicron. We applied this model to screen 2100 compounds from targeted drug libraries using a high throughput-high content image-based quantification method. Results The model recapitulated the heterogeneity of infection among patients with SARS-CoV-2 parental strain and variants. While there were heterogeneous responses across variants for host factor targeting compounds, the two direct-acting antivirals we tested, Remdesivir and Paxlovid, showed consistent efficacy in reducing infection across all variants and donors. Using the model, we characterized a new antiviral drug effective against both the parental strain and the Omicron variant. Conclusion This study demonstrates that the 96-well ALI model of primary human mucociliary epithelium can recapitulate the heterogeneity of infection among different donors and SARS-CoV-2 variants and can be used for moderate throughput screening. Compounds that target host factors showed variability among patients in response to SARS-CoV-2, while direct-acting antivirals were effective against SARS-CoV-2 despite the heterogeneity of patients tested.

ABSTRACT Numerous host factors, in addition to human angiotensin-converting enzyme 2 (hACE2), have been identified as coreceptors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrating broad viral tropism and diversified druggable potential. We and others have found that antihistamine drugs, particularly histamine receptor H1 (HRH1) antagonists, potently inhibit SARS-CoV-2 infection. In this study, we provided compelling evidence that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding to the viral spike protein. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor. Multiple inhibition assays revealed that antihistamine drugs broadly inhibited the infection of various SARS-CoV-2 mutants with an average IC50 of 2.4 µM. The prophylactic function of these drugs was further confirmed by authentic SARS-CoV-2 infection assays and humanized mouse challenge experiments, demonstrating the therapeutic potential of antihistamine drugs for combating coronavirus disease 19. IMPORTANCE In addition to human angiotensin-converting enzyme 2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can utilize alternative cofactors to facilitate viral entry. In this study, we discovered that histamine receptor H1 (HRH1) not only functions as an independent receptor for SARS-CoV-2 but also synergistically enhances ACE2-dependent viral entry by directly interacting with ACE2. Further studies have demonstrated that HRH1 facilitates the entry of SARS-CoV-2 by directly binding to the N-terminal domain of the spike protein. Conversely, antihistamine drugs, primarily HRH1 antagonists, can competitively bind to HRH1 and thereby prevent viral entry. These findings revealed that the administration of repurposable antihistamine drugs could be a therapeutic intervention to combat coronavirus disease 19.

Background and Objectives This study was aimed to determine the effect of antihistamines on Covid-19 disease. Subjects and Methods Two researchers searched online electronic databases PubMed, MEDLINE and Google Scholar from the beginning of the pandemic until December 30, 2022 using Mesh and keywords such as: "SARS-CoV-2" or "COVID-19" and "Antihistamine". Results The results depicted that levocetirizine, diphenhydramine, hydroxyzine, azelastine, dexchlorpheniramine, cetirizine, loratadine, desloratadine, fexofenadine, triprolidine, dimetindene, and famotidine are effective in treating and reducing the symptoms of Covid-19. Among them, famotidine had contradictory results, and although it may be a useful supplement in the treatment of covid-19, laboratory studies have failed to show the direct role of famotidine in controlling this disease. Conclusion From the above-discussed findings regarding antihistamines and Covid-19, specific antihistamines should be identified and included as an essential therapeutic approach for the management of Covid-19 alongside other approaches. In fact, antihistamines appear to be promising in the management of Covid-19 with a short time to relieve symptoms while giving the body enough time to reset its defense mechanism, thus reaching a rapid recovery. They work by both modulating histamine pathways and suppressing virus growth. Despite the fact that more trials and clinical studies still need to be done on the identification and deployment of potential antihistamines in the management of Covid-19, there is not enough time for this given the enormous threat of this global health crisis. Selective antihistamines, particularly histamine H1 receptor antagonists, should now be approved for emergency use for the management of Covid-19.

The emergence of lethal coronaviruses follows a periodic pattern which suggests a recurring cycle of outbreaks. It remains uncertain as to when the next lethal coronavirus will emerge, though its eventual emergence appears to be inevitable. New mutations in evolving SARS-CoV-2 variants have provided resistance to current antiviral drugs, monoclonal antibodies, and vaccines, reducing their therapeutic efficacy. This underscores the urgent need to investigate alternative therapeutic approaches. Sigma receptors have been unexpectedly linked to the SARS-CoV-2 life cycle due to the direct antiviral effect of their ligands. Coronavirus-induced cell stress facilitates the formation of an ER-derived complex conducive to its replication. Sigma receptor ligands are believed to prevent the formation of this complex. Repurposing FDA-approved drugs for COVID-19 offers a timely and cost-efficient strategy to find treatments with established safety profiles. Notably, diphenhydramine, a sigma receptor ligand, is thought to counteract the virus by inhibiting the creation of ER-derived replication vesicles. Furthermore, lactoferrin, a well-characterized immunomodulatory protein, has shown antiviral efficacy against SARS-CoV-2 both in laboratory settings and in living organisms. In the present study, we aimed to explore the impact of sigma receptor ligands on SARS-CoV-2-induced mortality in ACE2-transgenic mice. We assessed the effects of an investigational antiviral drug combination comprising a sigma receptor ligand and an immunomodulatory protein. Mice treated with sigma-2 receptor ligands or diphenhydramine and lactoferrin exhibited improved survival rates and rapid rebound in mass following the SARS-CoV-2 challenge compared to mock-treated animals. Clinical translation of these findings may support the discovery of new treatment and research strategies for SARS-CoV-2.

AbstractThe recent outbreak of the COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has shown the necessity for fast and broad drug discovery methods to enable us to react quickly to novel and highly infectious diseases. A well-known SARS-CoV-2 target is the viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication, which is essential for the viral life cycle. Here, we applied an interaction-based drug repositioning algorithm on all protein-compound complexes available in the protein database (PDB) to identify Mpro inhibitors and potential novel compound scaffolds against SARS-CoV-2. The screen revealed a heterogeneous set of 692 potential Mpro inhibitors containing known ones such as Dasatinib, Amodiaquine, and Flavin mononucleotide, as well as so far untested chemical scaffolds. In a follow-up evaluation, we used publicly available data published almost two years after the screen to validate our results. In total, we are able to validate 17% of the top 100 predictions with publicly available data and can furthermore show that predicted compounds do cover scaffolds that are yet not associated with Mpro. Finally, we detected a potentially important binding pattern consisting of 3 hydrogen bonds with hydrogen donors of an oxyanion hole within the active side of Mpro. Overall, these results give hope that we will be better prepared for future pandemics and that drug development will become more efficient in the upcoming years.