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New strategies of bioconjugation for the synthesis of multifunctional bioconjugates
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Resumo(s)
The recurrent discovery of new drug targets demanding innovative therapeutic agents further increases the need for new, highly selective, and active substances for future therapeutic applications. In this regard, chemical modification of peptides and proteins has emerged, and the significant progress accomplished in this field over the years allowed for the development of an extensive toolbox of bioconjugation technologies that enabled the creation of almost unlimited peptide and protein constructs with either naturally or synthetically modified residues. Recently, there has been a notable increase in interest in peptide-drug conjugates within the pharmaceutical industry. This is because peptides not only have relevant therapeutic applications but are also simple in design, relatively easy to synthesize and cost-effective. Moreover, researchers have been striving to develop multivalent reagents with the aim of creating bioconjugates with multiple functions with higher order of structural and functional complexity that aim to optimize biological studies and applications in vitro and in vivo. In this context, this thesis provides valuable insight into the construction of a new class of multivalent bioconjugation reagents for orthogonal functionalization of peptides at N terminal cysteines. These reagents, based on NHS-activated acrylates, present dual substitution and showed to site-selectively modify native peptides at the N-terminal cysteine, under biocompatible conditions in the micromolar range, without cross reacting with Lys, His, Ser, Thr, Tyr and in-chain Cys residues, resulting in stable bioconjugates. Furthermore, a Cys-bombesin peptide-drug conjugate was developed functionalized with a PEG chain, a coumarin probe and a cytotoxic drug, and was effectively used to label HeLa cells. Additionally, the pharmaceutical industry is also keen on investing in the development of effective drug delivery systems for the controlled administration of pre-existing drugs. In this thesis, we provide initial findings on the development of surface-modified particles in drug powder formulations.
Descrição
Palavras-chave
Bioconjugação seletividade posicional reagentes ortogonais multifuncionais conjugados fármaco-péptido sistemas avançados de entrega de fármaco Bioconjugation site-selectivity multivalent orthogonal reagents peptide-drug conjugate advanced drug delivery systems