title: A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion.
abstract: LJ001 is a lipophilic thiazolidine derivative that inhibits the entry of numerous enveloped viruses at non-cytotoxic concentrations (IC50 ≤ 0.5 µM), and was posited to exploit the physiological difference between static viral membranes and biogenic cellular membranes. We now report on the molecular mechanism that results in LJ001's specific inhibition of virus-cell fusion. The antiviral activity of LJ001 was light-dependent, required the presence of molecular oxygen, and was reversed by singlet oxygen ((1)O2) quenchers, qualifying LJ001 as a type II photosensitizer. Unsaturated phospholipids were the main target modified by LJ001-generated (1)O2. Hydroxylated fatty acid species were detected in model and viral membranes treated with LJ001, but not its inactive molecular analog, LJ025. (1)O2-mediated allylic hydroxylation of unsaturated phospholipids leads to a trans-isomerization of the double bond and concurrent formation of a hydroxyl group in the middle of the hydrophobic lipid bilayer. LJ001-induced (1)O2-mediated lipid oxidation negatively impacts on the biophysical properties of viral membranes (membrane curvature and fluidity) critical for productive virus-cell membrane fusion. LJ001 did not mediate any apparent damage on biogenic cellular membranes, likely due to multiple endogenous cytoprotection mechanisms against phospholipid hydroperoxides. Based on our understanding of LJ001's mechanism of action, we designed a new class of membrane-intercalating photosensitizers to overcome LJ001's limitations for use as an in vivo antiviral agent. Structure activity relationship (SAR) studies led to a novel class of compounds (oxazolidine-2,4-dithiones) with (1) 100-fold improved in vitro potency (IC50<10 nM), (2) red-shifted absorption spectra (for better tissue penetration), (3) increased quantum yield (efficiency of (1)O2 generation), and (4) 10-100-fold improved bioavailability. Candidate compounds in our new series moderately but significantly (p≤0.01) delayed the time to death in a murine lethal challenge model of Rift Valley Fever Virus (RVFV). The viral membrane may be a viable target for broad-spectrum antivirals that target virus-cell fusion.
authors: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Frederic
authors: F
authors: Vigant
authors: Jihye
authors: J
authors: Lee
authors: Axel
authors: A
authors: Hollmann
authors: Lukas B
authors: LB
authors: Tanner
authors: Zeynep
authors: Z
authors: Akyol Ataman
authors: Tatyana
authors: T
authors: Yun
authors: Guanghou
authors: G
authors: Shui
authors: Hector C
authors: HC
authors: Aguilar
authors: Dong
authors: D
authors: Zhang
authors: David
authors: D
authors: Meriwether
authors: Gleyder
authors: G
authors: Roman-Sosa
authors: Lindsey R
authors: LR
authors: Robinson
authors: Terry L
authors: TL
authors: Juelich
authors: Hubert
authors: H
authors: Buczkowski
authors: Sunwen
authors: S
authors: Chou
authors: Miguel A R B
authors: MA
authors: Castanho
authors: Mike C
authors: MC
authors: Wolf
authors: Jennifer K
authors: JK
authors: Smith
authors: Ashley
authors: A
authors: Banyard
authors: Margaret
authors: M
authors: Kielian
authors: Srinivasa
authors: S
authors: Reddy
authors: Markus R
authors: MR
authors: Wenk
authors: Matthias
authors: M
authors: Selke
authors: Nuno C
authors: NC
authors: Santos
authors: Alexander N
authors: AN
authors: Freiberg
authors: Michael E
authors: ME
authors: Jung
authors: Benhur
authors: B
authors: Lee
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002462:Cell Membrane / Q000187:drug effects / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D010080:Oxazoles / Q000494:pharmacology*; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D017319:Photosensitizing Agents / Q000494:pharmacology; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012295:Rift Valley Fever / Q000188:drug therapy; D012296:Rift Valley fever virus / Q000187:drug effects*; D026082:Singlet Oxygen / Q000737:chemistry; D013329:Structure-Activity Relationship; D013871:Thiones / Q000494:pharmacology*; D053585:Virus Attachment / Q000187:drug effects*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C549213:LJ001 compound; D010080:Oxazoles; D010743:Phospholipids; D017319:Photosensitizing Agents; D013871:Thiones; D026082:Singlet Oxygen; D012236:Rhodanine
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