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Galinus, L. Logan, R. DeHovitz, and Y. Mal- tivity against entry of the related paramyxovirus HPIV-2 or of donado. Deficiency of the humoral immune response to measles vac- the lentivirus HIV-1, demonstrating the target specificity of cine in infants immunized at age 6 months. JAMA — Garrett, R. Biochemistry, 3rd ed. Thomson Learning, Inc. Hilleman, M. Current overview of the pathogenesis and prophylaxis signed to dock into a microdomain in the MV F protein that we of measles with focus on practical implications.

Vaccine — Jang, M. Cai, G. Udeani, K. Slowing, C. Thomas, C. Beecher, Plemper, R. Hammond, and R. Measles virus H. Fong, N. Farnsworth, A. Kinghorn, R. Mehta, R. Moon, envelope glycoproteins hetero-oligomerize in the endoplasmic reticulum. Cancer chemopreventive activity of resveratrol, a J. Science — Hammond, D. Gerlier, A. Fielding, and R. Jansen, V. Stollenwerk, H. Jensen, M. Ramsay, W. Edmunds, Strength of envelope protein interaction modulates cytopathicity of and C. Measles outbreaks in a population with declining measles virus.

Science Lakdawala, K. Gernert, J. Snyder, and R. Kaya, I. Synthesis, characterization, and optimum reaction conditions Compans. Polymer Anal. Biochemistry — Polack, F. Lee, S. Permar, E. Manyara, H. Nousari, Y. Jeng, F. Kizhatil, K. Requirements for different compo- Mustafa, A. Valsamakis, R. Adams, H. Robinson, and D. Successful DNA immunization against measles: neutralizing antibody virus entry via endocytosis from entry via surface fusion. Lamb, R. Paramyxovirus fusion: a hypothesis for changes.

Virology Putz, M. Bouche, R. Exper- — Paramyxoviridae: the viruses and their Parasitol. Knipe and P. Howley ed. Rapaport, D. Ovadia, and Y. A synthetic peptide correspond- virology, 4th ed. Lambert, D. Barney, A. Lambert, K. Guthrie, R. Medinas, D. Bucy, J. Erickson, G. Merutka, and S. Petteway, Jr. EMBO J. Peptides from conserved regions of paramyxovirus fusion F proteins are Roche, M.

Dufour, N. Mora, and O. Antioxidant activity potent inhibitors of viral fusion. Longini, I. Halloran, A. Nizam, and Y. Containing products by mass spectrometry. Rota, P. Update on the global distribution of Mossong, J. Nokes, W. Edmunds, M. Cox, S. Ratnam, and C. Modeling the impact of subclinical measles transmission in S Starr-Spires, L. HIV-1 entry and entry inhib- Modelling antibody response to measles vaccine and subsequent waning of immunity in a low Tatsuo, H.

Ono, K. Tanaka, and Y. Nature — Naniche, D. Varior-Krishnan, F. Cervoni, T. Wild, B. Rossi, C. Ra- Ono, and Y. Morbilliviruses use signaling lym- bourdin-Combe, and D. Human membrane cofactor protein phocyte activation molecules CD as cellular receptors. Norrby, E. The effect of a carbobenzoxy tripeptide on the biological Vinson, J.

Su, L. Zubik, and P. Phenol antioxidant quantity activities of measles virus. Virology — Food Chem. Oldstone, M. Homann, H. Lewicki, and D. One, two, Weiss, W. Murphy, M. Lynch, J. Frye, A. Buklan, B. Gray, E. Lenoy, or three step: measles virus receptor dance.

Mitelman, J. Quartuccio, and C. Inhalation Yan, X. Murphy, G. Hammond, J. Vinson, and C. Erlandson, A. Lakdawala, A. Sun, A. Prussia, J. Antioxidant activities and antitumor screening of extracts from cranberry Boonsombat, E. Aki-Sener, I. Yalcin, I. Yildiz, O. Temiz-Arpaci, B. Tekiner, fruit Vaccinium macrocarpon. Liotta, J. A target site for Yao, Q. Peptides corresponding to the heptad template-based design of measles virus entry inhibitors.

Characterization of Young, J. Hicks, G. Wright, and T. Analysis a region of the measles virus hemagglutinin sufficient for its dimerization. NMR, and molecular modeling. Oncolytic measles virus strains as novel anticancer agents By Mateusz Opyrchal. Efficient replication of a paramyxovirus independent of full zippering of the fusion protein six-helix bundle domain By Richard Plemper.

Antiviral effects of 6-diazooxo-l-norleucin on replication of herpes simplex virus type 1 By Hana Kabickova. Antiviral activity of gliotoxin, gentian violet and brilliant green against Nipah and Hendra virus in vitro By Hendra G. Engineered measles virus as a novel oncolytic therapy against prostate cancer By louis galanis. Maleic anhydride-modified chicken ovalbumin as an effective and inexpensive anti-HIV microbicide candidate for prevention of HIV sexual transmission By lu lu.

A cell based high-throughput screening approach for the discovery of new inhibitors of respiratory syncytial virus By Colleen Jonsson. Oncolytic measles viruses displaying a single-chain antibody against CD38, a myeloma cell marker By Roberto Cattaneo.

Comparison of the inhibition of human metapneumovirus and respiratory syncytial virus by NMSO3 in tissue culture assays By Edina Moylett. Therapies for coronaviruses. Furthermore, addition of the compound after particle absorption and low-pH treatment resulted in only a small reduction in virus yield, confirming that postentry steps of the viral life cycle are not targeted by AS Fig.

The reduced extent of inhibition in sample C compared to control cells treated with AS before and after the pH shock Fig. These assumptions were confirmed by control samples in which AS was replaced by fusion inhibitory peptide FIP , a peptidic inhibitor of MV entry 18 that has been demonstrated previously to interfere with MV infection Fig.

Taken together, these findings support the conclusion that AS acts at the level of MV entry. Dose-response curves showing virus yields obtained after incubation in the presence of different compound concentrations reveal an IC 50 for AS against MV-KS of 0.

These findings thus suggest the high target specificity of AS and furthermore argue against residual cytotoxicity contributing to its inhibitory activity, since compound-mediated cytotoxicity would act nonspecifically and hence reduce yields of other viruses such as HPIV AS shows high target specificity. Average values of two experiments are shown. To further assess its potency against a representative panel of primary MV strains, we generated dose-response curves for viruses representing a relevant subset of genotypes that are currently active worldwide 30 and calculated IC 50 values for each isolate Fig.

AS is active against a representative panel of wild-type MV isolates. For comparison, the vaccine strain MV-Edm genotype A was included. Values indicate IC 50 concentrations that were calculated on the basis of these inhibition curves.

AS consistently demonstrated strong activity against all wild-type strains tested in this experiment, with IC 50 values ranging from 0. Consistent with our previous observations for the first-hit compound OX-1 21 , the lower sensitivity of the vaccine strain to inhibition by AS may be at least partially due to a methionine-to-valine mutation at position 94 of the MV-Edm F protein.

All wild-type strains analyzed so far contain a methionine residue at this position. We describe the development of a potent and stable small-molecule inhibitor of MV entry, AS This compound was designed on the basis of our previously reported MV entry inhibitor AM-4, which has strong antiviral activity but lacks stability. AS demonstrates greatly improved stability under physiologic conditions, shows low cytotoxicity, and has potent antiviral activity, with an IC 50 ranging from 0.

It is well known that several 1,2-, 1,3-, and 1,4-dihydroxybenzene analogs pyrocatechol, resorcinol, and hydroquinone, respectively are powerful antioxidants in fruits 34 , 36 , oils 29 , and wine 7. Furthermore, the hydroquinone coenzyme Q ubiquinol is the membrane-sequestered small-molecule mediator of electron transport in the inner membrane of the mitochondria 5.

Similarly, para -hydroxyanilines are also strong reducing agents that are readily air oxidized to quinones and related polymers 9. Consequently, the short half-life of AM-4 in air is understandable by analogy. We have thus attempted to introduce chemical stability, retain overall compound geometry, and present similar pharmacophoric elements compared to AM-4 in alternative structures.

The nonplanar geometry of AM-4 21 arises from the CH 2 group serving as a fulcrum in the center of the molecule. It is retained in AS, as is the hydrophobic phenyl ring that we found to be critical for antiviral activity The former is replaced by an amide, the latter by a nitro group in AS As a result, the reducing capacity of the ring has been blocked. Indeed, the stability of AS was confirmed experimentally both by HPLC and NMR, and by the fact that preincubation at physiologic conditions for 16 h caused negligible reduction of its antiviral activity.

AS inhibits cell-to-cell fusion induced by the H and F proteins of a currently prevalent genotype D5 strain, MV-KS 30 , and does not interfere with postentry steps of the virus life cycle. Furthermore, our data suggest that AS, like AM-4 and OX-1, inhibits the membrane fusion step in the viral entry process, rather than interfering with the attachment of virus to target cells.

IC 50 values ranging from 0. AS and its predecessors AM-4 and OX-1 were all designed to dock into a microdomain in the MV F protein that we have previously described as important for the fusion process 21 , In previous work, we identified several mutations in this cavity and elsewhere in the F protein that conferred resistance to inhibition.

One of these residues is amino acid 94, which is a valine in the MV-Edm vaccine strain and a methionine in all other strains analyzed thus far. MV-Edm shows a reduced susceptibility to inhibition with both AS and OX-1, suggesting a role for this residue in determining sensitivity to inhibition by this family of inhibitors. Consistent with this observation, substituting valine for methionine in MV-Edm conferred increased sensitivity to AS on a recombinant virus.

We reason that the development of small-molecule measles virus inhibitors that can be produced cost-effectively may be highly beneficial in complementing the existing measles vaccination program by rapidly controlling local outbreaks and augmenting management of severe cases of measles. Since MV infects through the respiratory route and our compounds or derivatives thereof could easily be aerosolized for oral administration, we furthermore consider a prophylactic application as an attractive future possibility.

We predict that viral spread could be drastically reduced in a setting similar to the recent outbreaks reported in the United Kingdom if an effective inhibitor were made available prophylactically to nonimmunized individuals in direct contact with identified index cases. Indeed, computer simulation models have demonstrated that an influenza pandemic could be blocked at the onset if antiviral drugs were administered to susceptible contacts of index cases Based on its activity against a range of measles virus strains currently circulating worldwide, we hypothesize that AS may have significant potential as a therapeutic lead inhibitor.

The potent in vitro antiviral activity of AS reported here supports further testing in vivo to assess the candidacy of AS for clinical development. We are grateful to A. Vzorov for testing of compound activity against HIV-1 and to L. White for critical reading of the manuscript. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of CDC.

Antimicrob Agents Chemother. Richard K. Rota , 3 Dennis C. Liotta , 2 James P. Snyder , 2 and Richard W. Compans 1. Paul A. Dennis C. James P. Richard W. Author information Article notes Copyright and License information Disclaimer. Phone: Fax: E-mail: ude. This article has been cited by other articles in PMC. Abstract The incidence of measles virus MV infection has been significantly reduced in many nations through extensive vaccination; however, the virus still causes significant morbidity and mortality in developing countries.

Compound synthesis. Compound stability assays. Compound screen, cytotoxicity, and dose-response curves. Isolation of envelope glycoproteins from primary MV isolates. Transient-inhibition assays. Membrane protection assays. Open in a separate window. Development of a stable lead inhibitor.

Characterization of inhibitor candidate AS Activity of AS against relevant wild-type MV isolates. Acknowledgments We are grateful to A. Centers for Disease Control and Prevention. Progress in reducing measles mortality—worldwide, Cianci, C.

Langley, D. Dischino, Y. Sun, K. Yu, A. Stanley, J. Roach, Z. Li, R. Dalterio, R. Colonno, N. Meanwell, and M. Targeting a binding pocket within the trimer-of-hairpins: small-molecule inhibition of viral fusion. USA : Dorig, R. Marcil, A. Chopra, and C. The human CD46 molecule is a receptor for measles virus Edmonston strain.

Cell 75 : Gans, H. Arvin, J. Galinus, L. Logan, R. DeHovitz, and Y. Deficiency of the humoral immune response to measles vaccine in infants immunized at age 6 months. JAMA : Garrett, R. Biochemistry , 3rd ed. Thomson Learning, Inc. Hilleman, M. Current overview of the pathogenesis and prophylaxis of measles with focus on practical implications. Vaccine 20 : Jang, M. Cai, G. Udeani, K. Slowing, C. Thomas, C.

Beecher, H. Fong, N. Farnsworth, A. Kinghorn, R. Mehta, R. Moon, and J. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science : Jansen, V. Stollenwerk, H. Jensen, M. Ramsay, W.

Edmunds, and C. Measles outbreaks in a population with declining vaccine uptake. Kaya, I. Polymer Anal. Kizhatil, K. Requirements for different components of the host cell cytoskeleton distinguish ecotropic murine leukemia virus entry via endocytosis from entry via surface fusion. Lamb, R. Paramyxovirus fusion: a hypothesis for changes. Virology : Paramyxoviridae: the viruses and their replication, p.

Knipe and P. Howley ed. Lambert, D. Barney, A. Lambert, K. Guthrie, R. Medinas, D. Davis, T. Bucy, J. Erickson, G. Merutka, and S. Petteway, Jr. Peptides from conserved regions of paramyxovirus fusion F proteins are potent inhibitors of viral fusion. USA 93 : Longini, I. Halloran, A. Nizam, and Y. Containing pandemic influenza with antiviral agents. Mossong, J. Nokes, W. Edmunds, M.

Cox, S. Ratnam, and C. Modeling the impact of subclinical measles transmission in vaccinated populations with waning immunity. O'Callaghan, and S. Modelling antibody response to measles vaccine and subsequent waning of immunity in a low exposure population. Vaccine 19 : Naniche, D. Varior-Krishnan, F. Cervoni, T. Wild, B. Rossi, C. Rabourdin-Combe, and D.

Human membrane cofactor protein CD46 acts as a cellular receptor for measles virus. Norrby, E. The effect of a carbobenzoxy tripeptide on the biological activities of measles virus. Virology 44 : Oldstone, M. Homann, H. Lewicki, and D. One, two, or three step: measles virus receptor dance.

Plemper, R. Mutations in the putative HR-C region of the measles virus F2 glycoprotein modulate syncytium formation. Erlandson, A. Lakdawala, A. Sun, A. Prussia, J. Boonsombat, E. Aki-Sener, I. Yalcin, I. Yildiz, O.

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Emanyara investing for beginners Because of loss of mechanical stability, these giant cells detach from the plate and cease to be metabolically active. Furthermore, the hydroquinone coenzyme Q click is the membrane-sequestered small-molecule mediator of electron transport in the inner membrane of the mitochondria 5. Lakdawala, K. This observation was corroborated by high-performance liquid chromatography HPLC analysis of the compound subse- quent to a hour incubation period and by NMR sampling over a hour period data not shown. Measles outbreaks also occur in some developed countries that have failed to maintain high vaccine coverage rates. Moon, envelope glycoproteins hetero-oligomerize in the endoplasmic reticulum. Stollenwerk, H.

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