RESUMEN
A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.
Asunto(s)
Biblioteca de Péptidos , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Proteínas Virales/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Aminoácidos/química , ADN/química , Evaluación Preclínica de Medicamentos/métodos , Terapia Molecular Dirigida , Péptidos Cíclicos/genética , Reacción en Cadena de la Polimerasa , Virus Sincitiales Respiratorios , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/química , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/químicaRESUMEN
The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.