2. Academic Validation
  3. Iterative Structure-Based Optimization of Short Peptides Targeting the Bacterial Sliding Clamp

Iterative Structure-Based Optimization of Short Peptides Targeting the Bacterial Sliding Clamp

  • J Med Chem. 2021 Dec 9;64(23):17063-17078. doi: 10.1021/acs.jmedchem.1c00918.
Clément Monsarrat 1,  Guillaume Compain 1,  Christophe André 1,  Sylvain Engilberge 2,  Isabelle Martiel 2,  Vincent Oliéric 2,  Philippe Wolff 3,  Karl Brillet 3,  Marie Landolfo 3,  Cyrielle Silva da Veiga 3,  Jérôme Wagner 4,  Gilles Guichard 1,  Dominique Y Burnouf 3
Affiliations

Affiliations

  • 1 Université de Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, F-33607 Pessac, France.
  • 2 Swiss Light Source (SLS), Paul Scherrer Institute (PSI), Forschungstrasse 111, 5232 Villigen-PSI, Switzerland.
  • 3 Université de Strasbourg, CNRS, Architecture et Réactivité de l'ARN, UPR 9002, Institut de Biologie Moléculaire et Cellulaire du CNRS, 2 rue Conrad Roentgen, F-67000 Strasbourg, France.
  • 4 Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS/Université de Strasbourg, ESBS, 300 Boulevard Sébastien Brant, 67412 Illkirch, France.
PMID: 34806883 DOI: 10.1021/acs.jmedchem.1c00918
Abstract

The Bacterial DNA sliding clamp (SC), or replication processivity factor, is a promising target for the development of novel Antibiotics. We report a structure-activity relationship study of a new series of Peptides interacting within the Escherichia coli SC (EcSC) binding pocket. Various modifications were explored including N-alkylation of the peptide bonds, extension of the N-terminal moiety, and introduction of hydrophobic and constrained residues at the C-terminus. In each category, single modifications were identified that increased affinity to EcSC. A combination of such modifications yielded in several cases to a substantially increased affinity compared to the parent Peptides with Kd in the range of 30-80 nM. X-ray structure analysis of 11 peptide/EcSC co-crystals revealed new interactions at the peptide-protein interface (i.e., stacking interactions, hydrogen bonds, and hydrophobic contacts) that can account for the improved binding. Several compounds among the best Binders were also found to be more effective in inhibiting SC-dependent DNA synthesis.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z