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

Autor: Pessi A; PeptiPharma, Rome, Italy., Bixler SL; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA; Therapeutic Development Center, USAMRIID, Frederick, MD, 21702, USA., Soloveva V; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA; Therapeutic Development Center, USAMRIID, Frederick, MD, 21702, USA., Radoshitzky S; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA; Therapeutic Development Center, USAMRIID, Frederick, MD, 21702, USA., Retterer C; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA., Kenny T; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA., Zamani R; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA., Gomba G; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA., Gharabeih D; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA., Wells J; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA., Wetzel KS; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA., Warren TK; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA; Therapeutic Development Center, USAMRIID, Frederick, MD, 21702, USA., Donnelly G; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA., Van Tongeren SA; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA., Steffens J; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA., Duplantier AJ; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA; Therapeutic Development Center, USAMRIID, Frederick, MD, 21702, USA., Kane CD; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA; Therapeutic Development Center, USAMRIID, Frederick, MD, 21702, USA. Electronic address: christopher.d.kane.civ@mail.mil., Vicat P; Sanofi, Paris, France., Couturier V; Sanofi, Paris, France., Kester KE; Sanofi Pasteur, Swiftwater, PA, USA., Shiver J; Sanofi Pasteur, Swiftwater, PA, USA., Carter K; Sanofi, Cambridge, MA, USA., Bavari S; United States Army Medical Research Institute of Infectious Diseases (USAMRIID), 1425 Porter Street, Frederick, MD, 21702, USA. Electronic address: sina.bavari.civ@mail.mil.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2019 Nov; Vol. 171, pp. 104592. Date of Electronic Publication: 2019 Aug 29.
DOI: 10.1016/j.antiviral.2019.104592
Abstrakt: 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 GP 2 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 EC 50 s 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 to protect mice from lethal challenge of mouse-adapted Ebola virus. These data show that engineered peptides coupled with cholesterol can inhibit viral production, protect mice against lethal EBOV infection, and may be used to build novel therapeutics against EBOV.
(Published by Elsevier B.V.)
Databáze: MEDLINE
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