Adressierung von Protein‐Protein‐Wechselwirkungen durch niedermolekulare Verbindungen: ein Pro‐Pro‐Dipeptidmimetikum mit PPII‐Helixkonformation als Modul für die Synthese PRD‐bindender Liganden

Abstract

Das X markiert den Punkt, an dem die Aminosäure X (siehe Struktur; grau C, cyan H, blau N, rot O, gelb Doppelbindung) als Pro‐Pro‐Ersatz in zwei Peptide eingebaut werden konnte, die an die prolinreiche Motive erkennende Domäne Fyn‐SH3 binden, ohne ihre Bindungsfähigkeit zu gefährden. Das Dipeptidanalogon X, das in einer Polyprolin‐Typ‐II‐Helixkonformation fixiert ist, wurde durch stereoselektive Einführung einer Vinylidenbrücke in eine Diprolineinheit erzeugt.

Induced‐Fit Binding of a Polyproline Helix by a β‐Hairpin Peptide

“…Prolyl–π interactions have been proposed to be critical to the binding of polyproline helices, which are binding epitopes in a number of different protein–protein interactions, including recognition events with SH3 domains, WW domains, EVH1 domains, GYF domains, EUV domains, and the single‐domain profilin proteins 5. 6 These protein–protein interactions are involved in a wide range of signaling pathways,6, 7 and some are associated with disease states, including HIV infection, Alzheimer’s, and cancer,8–11 making them potential therapeutic targets 12–15. The recognition domains for polyproline helices contain an aromatic cleft in which at least one proline binds 5.…”

Triple‐Helix‐Stabilizing Effects in Collagen Model Peptides Containing PPII‐Helix‐Preorganized Diproline Modules

“…In the course of our previous studies aiming at the development of small‐molecule inhibitors of the PPII helix recognizing Ena/VASP homology 1 (EVH1) domain, we developed proline‐derived modules (ProMs) ProM1 and ProM2 (Figure ) . The design is based on the stereo‐defined covalent connection of two adjacent proline rings by a C 2 bridge to freeze the system in a PPII‐helix‐type conformation.…”

Silaproline Helical Mimetics Selectively Form an All‐trans PPII Helix

“…[14] While a-helices or b-turn mimics have been largely studied in the past, few approaches have been described that emulate the PPII structure. [15] Polyimidebased foldamers, [16] Ser-Pro dipeptide oligomer mimic [17] or tricyclic Pro-Pro mimic, [18] triproline mimics [19] and PTAAs [20] are among current PPII structural mimics, designed to modulate physical properties such as water solubility. In this context, a few years ago, we developed a silicon-containing proline surrogate, silaproline (Sip) [21] that promotes higher lipophilicity with an octanol-water coefficient of Sip 14 times greater than that of Pro.…”

“…A)18 Si NMR spectrum of dimer 2 in CD 3 OD at 298 K. B) ROESY spectrum of dimer 2 in CD 3 OD at 298 K. NOE correlations between a CH(i) and a CH(i + 1) in the cis conformer (600 MHz spectrometer, mixing time = 300 ms).…”