201. Structure-Stability-Function Mechanistic Links in the Anti-Measles Virus Action of Tocopherol-Derivatized Peptide Nanoparticles
- Author
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Diogo A. Mendonça, Anne Moscona, Ana Salomé Veiga, Miguel A. R. B. Castanho, Matteo Porotto, Diana Gaspar, Tiago N. Figueira, Manuel N. Melo, Figueira, Tiago N., Mendonça, Diogo A., Gaspar, Diana, Melo, Manuel N., Moscona, Anne, Porotto, Matteo, Castanho, Miguel A. R. B., Veiga, Ana Salomé, and Repositório da Universidade de Lisboa
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0301 basic medicine ,measles viru ,fusion inhibitor ,Cell ,General Physics and Astronomy ,Tocopherols ,Peptide ,Microbial Sensitivity Tests ,Virus Replication ,Metastable ,Antiviral Agents ,Article ,Measles virus ,03 medical and health sciences ,Physics and Astronomy (all) ,Nanoparticle ,Engineering (all) ,medicine ,General Materials Science ,Self-assembling ,Antiviral ,metastable ,Fusion inhibitor ,chemistry.chemical_classification ,biology ,nanoparticle ,General Engineering ,Entry into host ,biology.organism_classification ,Virology ,Fusion protein ,antiviral ,peptide ,self-assembling ,3. Good health ,Heptad repeat ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Lipophilicity ,Nanoparticles ,Materials Science (all) ,Glycoprotein ,Peptides ,Viral Fusion Proteins - Abstract
© 2018 American Chemical Society, Measles remains one of the leading causes of child mortality worldwide and is re-emerging in some countries due to poor vaccine coverage, concomitant with importation of measles virus (MV) from endemic areas. The lack of specific chemotherapy contributes to negative outcomes, especially in infants or immunodeficient individuals. Fusion inhibitor peptides derived from the MV Fusion protein C-terminal Heptad Repeat (HRC) targeting MV envelope fusion glycoproteins block infection at the stage of entry into host cells, thus preventing viral multiplication. To improve efficacy of such entry inhibitors, we have modified a HRC peptide inhibitor by introducing properties of self-assembly into nanoparticles (NP) and higher affinity for both viral and cell membranes. Modification of the peptide consisted of covalent grafting with tocopherol to increase amphipathicity and lipophilicity (HRC5). One additional peptide inhibitor consisting of a peptide dimer grafted to tocopherol was also used (HRC6). Spectroscopic, imaging, and simulation techniques were used to characterize the NP and explore the molecular basis for their antiviral efficacy. HRC5 forms micellar stable NP while HRC6 aggregates into amorphous, loose, unstable NP. Interpeptide cluster bridging governs NP assembly into dynamic metastable states. The results are consistent with the conclusion that the improved efficacy of HRC6 relative to HRC5 can be attributed to NP instability, which leads to more extensive partition to target membranes and binding to viral target proteins., This work was supported by Fundação para a Ciência e a Tecnologia (FCT-MCTES) Project PTDC/QEQ-MED/4412/2014. T.N.F., D.A.M,. and D.G. acknowledge individual fellowships SFRH/BD/5283/2013, PD/BD/ 136752/2018 and SFRH/BPD/109010/2015 funded by FCT-MCTES. A.S.V. acknowledges funding under the Investigator Programme (IF/00803/2012) from FCTMCTES. M.N.M. acknowledges Grant LISBOA-01-0145- FEDER-007660 (Microbiologia Molecular, Estrutural e Celular) funded by Fundo Europeu de Desenvolvimento Regional (FEDER) and FCT-MCTES. A.M. acknowledges Grants RO1AI114736, R33AI101333, and RO1AI031971, and M.P. acknowledges grants R01AI119762, R01AI121349, and R01NS105699 funded by the National Institutes of Health (NIH).
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- 2018