Lunatinas: um estudo da relação estrutura-função de peptídeos bioativos multifuncionais

• Ano de defesa: 2023
• Autor(a) principal: John Alexanders Amaya Parra
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais
• Palavras-chave em Português: Bioquímica e imunologia; Venenos de Escorpião; Peptídeos bioativos
• Link de acesso: https://hdl.handle.net/1843/84869

Lunatins are a family of peptides found in the venom of the scorpion Hadruroides lunatus, known for their various biological activities, including antimicrobial action, antitumor effects, and phosphatase inhibition. Among them, Lunatin-1 (L1) stands out as a hydrophobic peptide consisting of thirteen residues, notable for its antimicrobial, cell-penetrating, and antitumor activities. This thesis deepened the understanding of the relationships between the three-dimensional structure adopted by the peptide and its multiple biological functions. A sequence similarity of 70-85% was observed between the L1 peptide and peptides from the Temporin, Maximin, and Caerulein families, which are known to be antimicrobial. Cell viability tests on NHDF and HL-60 cell lines demonstrated that the substitution of glycine-4-alanine (L1-G4A) increased antitumor and cytotoxic activities, while the substitution of lysine-7-alanine (L1-K7A) resulted in loss of antitumor activity, without altering the activity profile of L1 peptide in NHDF cells. Other analogs showed a reduction of 25-75% in antitumor activity. Additionally, cytotoxic analogs were obtained for NHDF, with L1-T8A standing out. Therefore, we chose three analogs with diverse behaviors to evaluate the structure-function relationship through nuclear magnetic resonance (NMR) in different membrane-mimetic environments. While L1 presented a partially helical conformation with an uncoiled N-terminal end, L1-G4A exhibited a coiled α-helical structure in both mimetic environments. L1-T8A revealed α-helical coiling with a possibly less flexible N-terminal end. On the other hand, the L1-F12A analog showed greater amphipathicity and structural stability, although it exhibited a reduction in antitumor activity. These results highlight the importance of residue arrangement and structure in the activity of bioactive peptides, as well as in the rational design process of new peptides. These findings have promising implications in the development of bioactive peptides with targeted and specific activities for desired targets.