Disrupting Aberrant Protein–Protein Interactions with Conformationally Constrained Hydrocarbon α-Helical Mimetics

Información del proyecto

DREAMY

Identificador del acuerdo de subvención: 794053

DOI

10.3030/794053

Proyecto cerrado

Fecha de la firma de la CE 23 Febrero 2018

Fecha de inicio 10 Octubre 2018

Fecha de finalización 20 Diciembre 2020

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 195 454,80

Aportación de la UE

€ 195 454,80

Coordinado por

UNIVERSITY OF BRISTOL
United Kingdom

Objetivo

Many critical processes within cells, including those that control whether a cell lives and divides or dies, are mediated by protein–protein interactions (PPIs). In certain disease states, such as cancer, these interactions can become defective in a way where disruption of the interaction has therapeutic benefit. Replacement of one of the protein partners, which often have α-helical secondary structure, with a small molecule is one method of disruption; however, the interface can often be large and shallow, making the design of competitive small molecules challenging. The saving grace is that the interaction energy is usually dominated by the interactions of a few amino acid residues, which protrude from one or more faces of the α-helical peptide. The design of α-helical mimetics that are non-peptidic in nature and that can replicate the positioning of these hotspot residues has been an active area of research. The host laboratory has recently developed a method to prepare chains of substituted carbon atoms with complete control of absolute and relative configuration. Owing to the avoidance of syn-pentane interactions, the all-syn and alternating syn–anti contiguously substituted chains fold into well-defined helical and linear conformations. The positioning of the substituents could uniquely replicate a pattern of hotspot residues that cover two or more faces of an α-helical peptide. This project will explore this possibility through the design, preparation and testing of mimetics that target the Mcl-1/Noxa-B PPI, which controls apoptosis and has leucine, arginine, isoleucine, aspartic acid, and valine at positions 11, 12, 14, 16 and 18 as hotspot residues. The project merges cutting-edge synthetic organic chemistry, multiple forms of computation, including molecular mechanics, density functional theory, and molecular dynamics, NMR spectroscopy, and medicinal chemistry.

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › medicina básica › química medicinal
• ciencias naturales › ciencias químicas › química orgánica › hidrocarburo
• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias naturales › ciencias físicas › óptica › espectroscopia › espectroscopia de absorción
• ciencias naturales › ciencias químicas › química orgánica › aminas

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2017 - Individual Fellowships
  

Régimen de financiación

MSCA-IF-EF-ST - Standard EF

Convocatoria de propuestas

H2020-MSCA-IF-2017

Coordinador

UNIVERSITY OF BRISTOL

• Aportación neta de la UEn: € 195 454,80
• Dirección: BEACON HOUSE QUEENS ROAD ; BS8 1QU BRISTOL ; Reino Unido
• Región: South West (England) › Gloucestershire, Wiltshire and Bristol/Bath area › Bristol, City of
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 195 454,80