Cholesterol-conjugated stapled peptides inhibit Ebola and Marburg viruses in vitro and in vivo

作者：Antonello Pessi, Sandra L. Bixler, Veronica Soloveva, Sheli R. Radoshitzky, Cary Retterer, Tara Kenny, Rouzbeh Zamani, Glenn Gomba, Dima Gharabeih, Jay Wells, Kelly S. Wetzel, Travis K. Warren, Ginger Donnelly, Sean A. Van Tongeren, Jesse Steffens, Allen J. Duplantier, Christopher D. Kane, Pascale Vicat, Valerie Couturier, Kent E. Kester, John W. Shiver, Kara Carter, Sina Bavari · 发表于：Antiviral Research · 年份：2019 · DOI：10.1016/j.antiviral.2019.104592 · 被引用次数：36 · 研究领域：Viral Infections and Outbreaks Research、Hepatitis B Virus Studies、Viral Infections and Vectors

Filoviridae currently includes five official and one proposed genera. Genus Ebolavirus includes five established and one proposed ebolavirus species for Bombali virus (BOMV), Bundibugyo virus (BDBV), Ebola virus (EBOV), Reston virus (RESTV), Sudan virus (SUDV) and Taï Forest virus (TAFV), and genus Marburgvirus includes a single species for Marburg virus (MARV) and Ravn virus (RAVV). Ebola virus (EBOV) has emerged as a significant public health concern since the 2013–2016 Ebola Virus Disease outbreak in Western Africa. Currently, there are no therapeutics approved and the need for Ebola-specific therapeutics remains a gap. In search for anti-Ebola therapies we tested the idea of using inhibitory properties of peptides corresponding to the C-terminal heptad-repeat (HR2) domains of class I fusion proteins against EBOV infection. The fusion protein GP2 of EBOV belongs to class I, suggesting that a similar strategy to HIV may be applied to inhibit EBOV infection. The serum half-life of peptides was expanded by cholesterol conjugation to allow daily dosing. The peptides were further constrained to stabilize a helical structure to increase the potency of inhibition. The EC50s of lead peptides were in low micromolar range, as determined by a high-content imaging test of EBOV-infected cells. Lead peptides were tested in an EBOV lethal mouse model and efficacy of the peptides were determined following twice-daily administration of peptides for 9 days. The most potent peptide was able ...