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A Mechanistic Paradigm for Broad-Spectrum Antivirals that Target Virus-Cell Fusion
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نویسنده
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vigant f. ,lee j. ,hollmann a. ,tanner l.b. ,akyol ataman z. ,yun t. ,shui g. ,aguilar h.c. ,zhang d. ,meriwether d. ,roman-sosa g. ,robinson l.r. ,juelich t.l. ,buczkowski h. ,chou s. ,castanho m.a.r.b. ,wolf m.c. ,smith j.k. ,banyard a. ,kielian m. ,reddy s. ,wenk m.r. ,selke m. ,santos n.c. ,freiberg a.n. ,jung m.e. ,lee b.
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منبع
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plos pathogens - 2013 - دوره : 9 - شماره : 4
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چکیده
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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 (1o2) quenchers,qualifying lj001 as a type ii photosensitizer. unsaturated phospholipids were the main target modified by lj001-generated 1o2. hydroxylated fatty acid species were detected in model and viral membranes treated with lj001,but not its inactive molecular analog,lj025. 1o2-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 1o2-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 1o2 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. © 2013 vigant et al.
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آدرس
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department of microbiology,immunology and molecular genetics,university of california los angeles,los angeles,ca, United States, department of chemistry and biochemistry,university of california los angeles,los angeles,ca, United States, instituto de medicina molecular,faculdade de medicina da universidade de lisboa,lisbon, Portugal, department of biochemistry,yong loo lin school of medicine,national university of singapore,singapore,nus graduate school for integrative sciences and engineering (ngs),national university of singapore, Singapore, department of microbiology,immunology and molecular genetics,university of california los angeles,los angeles,ca, United States, department of pathology,university of texas medical branch,galveston,tx, United States, life sciences institute,national university of singapore,singapore,state key laboratory of molecular developmental biology,institute of genetics and developmental biology,chinese academy of sciences,beijing, China, paul g. allen school for global animal health,department of veterinary microbiology and pathology,washington state university,pullman,wa, United States, department of chemistry and biochemistry,california state university,los angeles,ca, United States, department of medicine,university of california los angeles,los angeles,ca, United States, department of cell biology,albert einstein college of medicine,bronx,ny,united states,department of internal medicine i,university of ulm,ulm, Germany, department of microbiology,immunology and molecular genetics,university of california los angeles,los angeles,ca, United States, department of pathology,university of texas medical branch,galveston,tx, United States, wildlife zoonoses and vector borne disease research group,animal health and veterinary laboratories agency,weybridge,surrey, United Kingdom, oregon health and science university and va medical center,portland,or, United States, instituto de medicina molecular,faculdade de medicina da universidade de lisboa,lisbon, Portugal, department of microbiology,immunology and molecular genetics,university of california los angeles,los angeles,ca,united states,defense threat reduction agency,fort belvoir,va, United States, department of pathology,university of texas medical branch,galveston,tx, United States, wildlife zoonoses and vector borne disease research group,animal health and veterinary laboratories agency,weybridge,surrey, United Kingdom, department of cell biology,albert einstein college of medicine,bronx,ny, United States, department of medicine,university of california los angeles,los angeles,ca, United States, department of biochemistry,yong loo lin school of medicine,national university of singapore,singapore,department of biological sciences,faculty of science,national university of singapore,singapore,swiss tropical and public health institute and university of basel,basel, Switzerland, department of chemistry and biochemistry,california state university,los angeles,ca, United States, instituto de medicina molecular,faculdade de medicina da universidade de lisboa,lisbon, Portugal, department of pathology,university of texas medical branch,galveston,tx, United States, department of chemistry and biochemistry,university of california los angeles,los angeles,ca, United States, department of microbiology,immunology and molecular genetics,university of california los angeles,los angeles,ca, United States
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Authors
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