Pesquisa

Self-association and folding in membrane

qua, 24 out 2018

Publicado por

Authors:

Ros, Uris1  ;  Carretero, Gustavo P. B.2 ;  Paulino, Joana2  ;  Crusca Jr., Edson3 ;  Pazos, Fabiola1 ;   Cilli, Eduardo M.3 ;  Lanio, Maria E.1 ;  Schreier, Shirley2 ;  Alvarez, Carlos1


Abstract:

Sticholysin I and II (Sts: St I and St II) are proteins of biomedical interest that form pores upon the insertion of their N-terminus in the plasma membrane. Peptides spanning the N-terminal residues of StI (StI1-31) or StII (StII1-30) can mimic the permeabilizing ability of these toxins, emerging as candidates to rationalize their potential biomedical applications. These peptides have different activities that correlate with their hydrophobicity. However, it is not clear how this property contributes to peptide folding in solution or upon binding to membranes. Here we compared the conformational properties of these peptides and shorter versions lacking the hydrophobic segment 1–11 of StI (StI12-31) or 1–10 of StII (StII11-30). Folding of peptides was assessed in solution and in membrane mimetic systems and related with their ability to bind to membranes and to permeabilize lipid vesicles. Our results suggest that the differences in activity among peptides could be ascribed to their different folding propensity and different membrane binding properties. In solution, StII1-30 tends to acquire α-helical conformation coexisting with self-associated structures, while StI1-31 remains structureless. Both peptides fold as α-helix in membrane; but StII1-30 also self-associates in the lipid environment, a process that is favored by its higher affinity for membrane. We stress the contribution of the non-polar/polar balance of the 1–10 amino acid sequence of the peptides as a determining factor for different self-association capabilities. Such difference in hydrophobicity seems to determine the molecular path of peptides folding upon binding to membranes, with an impact in their permeabilizing activity. This study contributes to a better understanding of the molecular mechanisms underlying the permeabilizing activity of Sts N-terminal derived peptides, with connotation for the exploitation of these small molecules as alternative of the full-length toxins in clinical settings.


1  Center for Protein Studies, Biology Faculty, University of Havana, Havana, Cuba

2  Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil

3  Department of Biochemistry, Institute of Chemistry, São Paulo State University, Araraquara, São Paulo, Brazil


Link to full article:   https://www.sciencedirect.com/science/article/pii/S0300908418302840

GA-Hecate antiviral properties

qua, 24 out 2018

Publicado por

Authors:

Batista, Mariana Nogueira1 ;   Sanches, Paulo Ricardo da Silva2 ;  Carneiro, Bruno Moreira1 ;  Braga, Ana Cláudia Silva1 ;   Campos, Guilherme Rodrigues Fernandes1 ;   Cilli, Eduardo Maffud2 ;  Paula Rahal1


Abstract:

In recent years, synthetic peptides have been considered promising targets for drug development that possess low side-effects, are cost-effective and are susceptible to rational design. Hecate was initially described as a potent bacterial inhibitor and subsequently as an anticancer drug with functions related to its lipid interaction property. Viruses, such as hepatitis C virus (HCV), have a lipid-dependent life cycle and could be affected by Hecate in many ways. Here, we assessed modifications on Hecate’s N-terminus region and its effects on HCV and hepatotoxicity. Gallic acid-conjugated Hecate was the most efficient Hecate-derivative, presenting high potential as an antiviral and inhibiting between 50 to 99% of all major steps within the HCV infectious cycle. However, the most promising aspect was GA-Hecate’s mechanism of action, which was associated with a balanced lipid interaction with the viral envelope and lipid droplets, as well as dsRNA intercalation, allowing for the possibility to affect other ssRNA viruses and those with a lipid-dependent cycle.


1  Institute of Bioscience, Language and Exact Science, UNESP – São Paulo State University, São José do Rio Preto, SP, Brazil

2  Institute of Chemistry, UNESP – São Paulo State University, Araraquara, SP, Brazil


Link to full article:  https://www.nature.com/articles/s41598-018-32176-w