Banca de DEFESA: PAULO PITASSE SANTOS

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : PAULO PITASSE SANTOS
DATE: 10/01/2022
TIME: 13:00
LOCAL: Apresentação em ambiente virtual, via Google Meet
TITLE:

Design, synthesis and biological assessment of peptides and peptide-drug conjugates with antibacterial and antiparasitic activity

KEY WORDS:

cell penetrating peptides, drug delivery, solid phase peptide synthesis, Trypanosoma cruzi

PAGES: 180
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Síntese Orgânica
SUMMARY:

Peptides are composed of amino acids linked in sequence and comprise a class of molecules of interest within medicinal chemistry. Both for their high selectivity for specific targets and for the complexity of their structures, which allow them to be applied for different purposes, such as antimicrobials or cell penetrating agents conjugated to drugs. Peptides and conjugates are potentially applicable in areas lacking therapeutic innovation, such as the development of new antibiotics for the treatment of multidrug-resistant bacteria or new chemotherapeutic agents for the treatment of Chagas disease. In this work, three series of cationic amphiphilic peptides are proposed with potential application as antimicrobials and cell penetrating peptides. The peptide-drug conjugation strategy with or without control of drug release in the intracellular environment is also evaluated using peptides of interest within the proposed series and the type II polyroline helix P14LRR, which has been reported as an antimicrobial and cell penetrating peptide. The synthesis of peptides and conjugates involved the use of classical organic synthesis techniques, with optimization of protocols found in the literature, as well as the solid phase peptide synthesis methodology. The drugs linezolid (Lnz) and benznidazole (Bzd) were used for the conjugation strategy. Peptide-drug conjugates connected via a spacer containing a disulfide bond, reducible in the intracellular medium, were evaluated for their chemically induced drug release kinetics. Additionally, the peptides and conjugates were evaluated against Escherichia coli for their antimicrobial activity and insights into the mechanisms of action. The design of the series made it possible to trace a structure-activity relationship, and the peptide Ac-YGRRLLRRLL-NH₂ was identified to be the most promising for this application (MIC = 2 µM). The activity against amastigotes and trypomastigotes of Trypanosoma cruzi was also evaluated. The peptide Ac-YGRRLLRRLLRRLLRRLL-NH₂ showed high effectiveness in inhibiting parasite infection in vitro (EC₅₀ = 299 ± 86 nM). Experiments were also carried out to evaluate the cell penetration potential of the Fl-YGRRLLRRLL-NH₂ peptide and the Lnz-Fl-P14LRR conjugate, both labeled with a fluorescein probe. They used flow cytometry and confocal microscopy techniques to verify the accumulation of compounds in the intracellular environment and, in the case of Lnz-Fl-P14LRR, indicating its placing in lysosomes at the subcellular level.

BANKING MEMBERS:
Presidente - 1058758 - MARCO EDILSON FREIRE DE LIMA
Interna - 1979542 - RENATA BARBOSA LACERDA
Externa ao Programa - 1335855 - DANIELLE DE OLIVEIRA NASCIMENTO
Externa à Instituição - NELILMA CORREIA ROMEIRO - UFRJ
Externa à Instituição - JULIANY COLA FERNANDES RODRIGUES - UFRJ
Externo à Instituição - ADRIANO DEFINI ANDRICOPULO - USP
Externo à Instituição - FERNANDO ANTÔNIO SANTOS COELHO - UNICAMP