| Autor: |
Figueira TN; Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , 1649-028 Lisbon , Portugal., Mendonça DA; Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , 1649-028 Lisbon , Portugal., Gaspar D; Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , 1649-028 Lisbon , Portugal., Melo MN; Instituto de Tecnologia Química e Biológica António Xavier , Universidade Nova de Lisboa , 2775-412 Oeiras , Portugal., Moscona A; Department of Pediatrics , Columbia University Medical Center , New York , New York 10032 , United States.; Center for Host-Pathogen Interaction , Columbia University Medical Center , New York , New York 10032 , United States.; Department of Microbiology & Immunology , Columbia University Medical Center , New York , New York 10032 , United States.; Department of Physiology & Cellular Biophysics , Columbia University Medical Center , New York , New York 10032 , United States., Porotto M; Department of Pediatrics , Columbia University Medical Center , New York , New York 10032 , United States.; Center for Host-Pathogen Interaction , Columbia University Medical Center , New York , New York 10032 , United States.; Department of Experimental Medicine , University of Campania 'Luigi Vanvitelli' , 81100 Caserta , Italy., Castanho MARB; Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , 1649-028 Lisbon , Portugal., Veiga AS; Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , 1649-028 Lisbon , Portugal. |
| Abstrakt: |
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. |
