Assuntos
Biblioteca Gênica , Compostos Macrocíclicos/química , Peptídeos Cíclicos/química , Peptidomiméticos/química , Bibliotecas de Moléculas Pequenas/química , Linhagem Celular , Ciclização , Descoberta de Drogas , Expressão Gênica , Humanos , Insulisina/antagonistas & inibidores , Insulisina/química , Compostos Macrocíclicos/metabolismo , Modelos Moleculares , Peptídeos Cíclicos/biossíntese , Peptidomiméticos/metabolismo , Mapeamento de Interação de Proteínas , Bibliotecas de Moléculas Pequenas/síntese químicaRESUMO
Macrocyclic natural products have evolved to fulfil numerous biochemical functions, and their profound pharmacological properties have led to their development as drugs. A macrocycle provides diverse functionality and stereochemical complexity in a conformationally pre-organized ring structure. This can result in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular locations. Despite these valuable characteristics, and the proven success of more than 100 marketed macrocycle drugs derived from natural products, this structural class has been poorly explored within drug discovery. This is in part due to concerns about synthetic intractability and non-drug-like properties. This Review describes the growing body of data in favour of macrocyclic therapeutics, and demonstrates that this class of compounds can be both fully drug-like in its properties and readily prepared owing to recent advances in synthetic medicinal chemistry.
Assuntos
Produtos Biológicos , Compostos Macrocíclicos , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/farmacocinética , Produtos Biológicos/uso terapêutico , Permeabilidade da Membrana Celular , Desenho de Fármacos , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/uso terapêuticoRESUMO
The mRNA display approach to in vitro protein selection is based upon the puromycin-mediated formation of a covalent bond between an mRNA and its gene product. This technique can be used to identify peptide sequences involved in macromolecular recognition, including those identical or homologous to natural ligand epitopes. To demonstrate this approach, we determined the peptide sequences recognized by the trypsin active site, and by the anti-c-Myc antibody, 9E10. Here we describe the use of two peptide libraries of different diversities, one a constrained library based on the trypsin inhibitor EETI-II, where only the six residues in the first loop were randomized (6.4 x 10(7) possible sequences, 6.0 x 10(11) sequences in the library), the other a linear-peptide library with 27 randomized amino acids (1.3 x 10(35) possible sequences, 2 x 10(13) sequences in the library). The constrained library was screened against the natural target of wild-type EETI, bovine trypsin, and the linear library was screened against the anti-c-myc antibody, 9E10. The analysis of selected sequences revealed minimal consensus sequences of PR(I,L,V)L for the first loop of EETI-II and LISE for the 9E10 epitope. The wild-type sequences, PRILMR for the first loop of EETI-II and QKLISE for the 9E10 epitope, were selected with the highest frequency, and in each case the complete wild-type epitope was selected from the library.