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1.
Bioorg Med Chem Lett ; 101: 129657, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360419

RESUMO

Herein, we report the modular synthesis and evaluation of a prostate-specific membrane antigen (PSMA) targeted small molecule drug conjugate (SMDC) carrying the chemotherapeutic agent, SN38. Due to the fluorogenic properties of SN38, payload release kinetics from the platform was observed in buffers representing the pH conditions of systemic circulation and cellular internalization. It was found that this platform is stable with minimal payload release at physiological pH with most rapid payload release observed at pH values representing the endosome complex. We confirmed selective payload release and chemotherapeutic efficacy for PSMA(+) prostate cancer cells over PSMA(-) cells. These results demonstrate that chemotherapeutic agents with limited solubility can be conjugated to a water-soluble targeting and linker platform without attenuating efficacy.


Assuntos
Glutamato Carboxipeptidase II , Neoplasias da Próstata , Masculino , Humanos , Linhagem Celular Tumoral , Glutamato Carboxipeptidase II/química , Antígenos de Superfície/química , Neoplasias da Próstata/tratamento farmacológico
2.
Science ; 381(6659): 754-760, 2023 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-37590357

RESUMO

In nature, proteins that switch between two conformations in response to environmental stimuli structurally transduce biochemical information in a manner analogous to how transistors control information flow in computing devices. Designing proteins with two distinct but fully structured conformations is a challenge for protein design as it requires sculpting an energy landscape with two distinct minima. Here we describe the design of "hinge" proteins that populate one designed state in the absence of ligand and a second designed state in the presence of ligand. X-ray crystallography, electron microscopy, double electron-electron resonance spectroscopy, and binding measurements demonstrate that despite the significant structural differences the two states are designed with atomic level accuracy and that the conformational and binding equilibria are closely coupled.


Assuntos
Engenharia de Proteínas , Cristalografia por Raios X , Ligantes , Engenharia de Proteínas/métodos , Conformação Proteica
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