Repurposing potential of 1st generation H1-specific antihistamines as anti-filovirus therapeutics

Abstract

Ebola and Marburg are filoviruses and biosafety level 4 pathogens responsible for causing severe hemorrhagic fevers in humans with mortality rates up to 90%. The most recent outbreak in West Africa resulted in approximately 11,310 deaths in 28,616 reported cases. Currently there are no FDA-approved vaccines or therapeutics to treat infections of these deadly viruses. Recently we screened an FDA-approved drug library and identified numerous G protein-coupled receptor (GPCR) antagonists including antihistamines possessing anti-filovirus properties. Antihistamines are attractive targets for drug repurposing because of their low cost and ease of access due to wide use. In this report we identify common over the counter antihistamines, such as diphenhydramine (Benadryl) and chlorcyclizine (Ahist) as potential candidates for repurposing as anti-filovirus agents. Furthermore, we demonstrate that this potential is wide-spread through the 1st generation of H-specific antihistamines but is not present in newer drugs or drugs targeting H, H and H receptors. We showed that the filovirus entry inhibition is not dependent on the classical antagonism of cell surface histamine or muscarinic acetylcholine receptors but occurs in the endosome, like the cathepsin inhibitor CA-074. Finally, using extensive docking studies we showed the potential for these drugs to bind directly to the EBOV-GP at the same site as toremifene. These findings suggest that the 1st generation antihistamines are excellent candidates for repurposing as anti-filovirus therapeutics and can be further optimized for removal of unwanted histamine or muscarinic receptor interactions without loss of anti-filovirus efficacy.

Identification of SARS-CoV-2 entry inhibitors among already approved drugs

“…Clemastine is used to relieve hay fever and allergy symptoms. Antihistamine drugs have been reported in the past to have certain antiviral effects [ 21 – 23 ]. In a previous report that used the SARS-CoV-2 viral protein interactome to identify antiviral drugs, Gordon et al reported that clemastine is an active antiviral agent targeting the Sigma 1 and Sigma 2 receptors [ 24 ].…”

A Panel of Broad-Spectrum Antivirals in Topical Ophthalmic Medications from the Drug Repurposing Approach during and after the Coronavirus Disease 2019 Era

“…Surprisingly, several antihistamines, such as chlorcyclizine, chlorpheniramine, and diphenhydramine, have demonstrated antiviral action against hepatitis C virus (HCV), filoviruses (consisting of Ebola virus, Marburg virus, and Cuevavirus), and Influenza A virus infection [78][79][80]. Of note, ketotifen fumarate has proven to attenuate dengue virus infection [81].…”

Identification of Diaryl-Quinoline Compounds as Entry Inhibitors of Ebola Virus

“…Most of these inhibitors target events occurring in the endosome, such as GP proteolytic processing, endosomal trafficking, interactions with NPC1, and fusion, including: (1) CA-074, FY-DMK, CID23631927, K11777, and cathepsin B and L inhibitors [29,30,37,38,39,40,41]; (2) inhibitors targeting host factors in the late endosomal steps in EBOV entry, such as U18666A, MBX2254, and MBX2270, targeting NPC1 [19,20,42], and numerous L-type calcium channel inhibitors, including verapamil, tetrandrine, nimodipinee, and diltiazem [10]; (3), a group of selective estrogen receptor modulators (SERMs), such as clomiphene and toremifene, which can directly bind to Ebola GP [36,43]; and (4) numerous G-protein coupled receptor (GPCR) antagonists such as antihistamines, targeting Ebola virus (and Marburg virus) GPs [34,44]. Only the first generation of antihistamines, such as diphenhydramine and chlorcyclizine, effectively block entry of Ebola virus and Marburg viruses, consistent with the notion that these compounds exert their antiviral effect in the endosomes [26].…”

“…We used a similar docking method as reported in our previous publication [26]. Briefly, the GLIDE module (Schrödinger 10.0, Portland, OR, USA) within Schrödinger Suite 2014 was used to rank the best conformations and orientations of the ligand based on its interactions with the Ebola virus GP (PDB code, 5JQ7) The LigPrep (including Ionizer) module and Macromodel module was used to generate three-dimensional coordinates of the ligands and protein with calculated ionization states.…”