RESUMO
Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer's disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems.
Assuntos
Sistema Nervoso Central/metabolismo , Chaperonas Moleculares/metabolismo , Mapeamento de Interação de Proteínas/instrumentação , Proteoma/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Glioblastoma/diagnóstico , Glioblastoma/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Sondas Moleculares/farmacologia , Sondas Moleculares/uso terapêutico , Tomografia por Emissão de PósitronsRESUMO
The jujubosides are saponin natural products reported to have immunoadjuvant, anticancer, antibacterial, antifungal, and antisweet activities. The triterpene component, jujubogenin contains a unique tricyclic ketal motif comprising the DEF ring system. Herein, we describe our efforts toward the total synthesis of jujubogenin, using a sterically-demanding intermolecular Diels-Alder reaction to assemble the C-ring and a tandem Wolff rearrangement-intramolecular ketene hetero-Diels-Alder reaction to form the DF-ring system. Acid-catalyzed cyclization of the resulting bicyclic enol ether then closes the E-ring to provide the hexacyclic core of jujubogenin.