Format

Send to

Choose Destination
Antiviral Res. 2018 Sep;157:47-56. doi: 10.1016/j.antiviral.2018.07.003. Epub 2018 Jul 4.

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

Author information

1
Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA. Electronic address: aschaf5@uic.edu.
2
Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
3
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, UICentre, University of Illinois at Chicago, Chicago, IL, 60612, USA.
4
US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, 21702, USA.
5
Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA; Zhiyuan College, Shanghai Jiao Tong University, Shanghai, 200240, China.
6
Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA. Electronic address: lijun@uic.edu.

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 H1-specific antihistamines but is not present in newer drugs or drugs targeting H2, H3 and H4 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.

KEYWORDS:

Antihistamine; Antiviral; Ebola; Marburg; Repurposing

PMID:
29981374
PMCID:
PMC6087678
DOI:
10.1016/j.antiviral.2018.07.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center