Designing peptide receptor agonists and antagonists

Abstract

The most ubiquitous mode for controlling and modulating cellular function, intercellular communication, immune response and information-transduction pathways is through peptide-protein non-covalent interactions. Hormones, neurotransmitters, antigens, cytokines and growth factors represent key classes of such peptide ligands. These ligands might either be processed fragments of larger precursor proteins or surface segments of larger proteins. Although there are numerous exceptions, such as insulin, oxytocin and calcitonin, most ligands are not used directly as drugs, and often the most useful ligands for therapy would be analogues that act as antagonists of the native ligands. A search for systematic structure-based or ligand-based approaches to designing such ligands has been an important concern. Today, a robust strategy has been developed for the design of peptides as drugs, drug candidates and biological tools. This strategy includes structural, conformational, dynamic and topographical considerations.

Parallel synthesis and biological evaluation of different sizes of bicyclo[2,3]‐Leu‐enkephalin analogues

“…The synthetic methods did not give all possible conformations, due to the lack of a robust methodology for varying the size and stereochemistry of the mimetics. Here we report a novel parallel synthetic strategy for [6,5]-and [7,5]-thiazolidinone bicyclo [2,3] -Leu-enkephalin analogues with different geometries using unconventional solid-phase synthesis ( Figure 1). In our synthesis, the ␤-side chains (R iϩ1 and R iϩ2 ) are not considered in amino acid precursors 4 and 5 because positions 2-3 in Leu-enkephalin are Gly-Gly.…”

“…The solid-phase synthesis of [6,5]-and [7,5]-bicyclo [2.3] -Leu-enkephalin was started using N ␣ -FmocLeu-Wang resin, by a strategy similar to that used in [5,5]-bicyclo [2.3] -Leu-enkephalin analogue synthesis (Scheme 2). The first two amino acids, phenylalanine and cysteine, were coupled using conventional methods.…”

“…Bicyclic dipeptide mimetics have been designed and synthesized in this area for over ten years. 9,10 Previous studies have found that a [5,5]-bicyclic mimetic could approximate a type II ␤-turn, 11,12 a [6,5]-bicyclic could closely mimic a type IIЈ ␤-turn, 12,13 while a [7,5]-bicyclic structure can lead to different reverse turn structures depending on the chirality. 14 However, introduction of these bicyclic scaffolds into peptides has been quite limited because multistep syntheses were required, but were difficult to accomplish.…”

“…15 Four bicyclo [2,3] -Leu-enkephalin analogues were prepared in parallel synthesis and their biological activities evaluated. Unfortunately, this simple and efficient methodology cannot be directly applied to [6,5]-and [7,5]-bicyclic dipeptide synthesis due to the formation of a 5-and 6-membered hemiaminal. 16,17 A novel methodology has to be developed here so that the synthesis can be performed on the solid-phase support.…”

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Abstract: Parallel synthesis of peptides and peptidomimetics has been an important approach to [6,[5][6][7]

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