Receptor-Targeting Small Molecule Inhibitors of Lassa and Ebola Virus Entry Reveal a Critical Role for Cholesterol in Regulating Receptor Activity

Abstract

Ebola virus (EBOV) and Lassa virus (LASV) are highly pathogenic hemorrhagic fever viruses endemic to Africa that represent a significant disease burden to human health in the area. Despite the severity of the diseases caused by the two viruses, current standard of care is mainly supportive as no approved and effective drugs or vaccines exist for either virus. In addition, although several vaccine candidates are currently under development for both viruses, the lack of public health infrastructure in Africa limits the effectiveness of vaccination as a prophylactic strategy and highlights the need for alternative post-exposure therapeutic interventions. Here we report the mechanisms of action of two related novel small molecule inhibitors of EBOV and LASV entry. Both compounds target cholesterol-binding sites within the viral host receptors, Niemann-Pick C1 and lysosome-associated membrane protein 1 respectively, and inhibit viral entry by preventing association of the viral envelope surface glycoproteins with their receptors. Using photoreactive inhibitor derivatives and characterization of resistant viruses, we uncover a critical role for cholesterol in regulating receptor activity and small molecule inhibition.