Structural Requirements for Molecular Recognition by fMLP Analogs Receptors: Comparative Conformational Analysis of (for-Met-Leu-Phe-OMe) and its Thioamide Analog (for-Met-Leuψ[CSNH]Phe-OMe)

Chakib Ameziane Hassani,Mourad Houssat,Ahmed Harrach,Jamal Eddine Hazm

doi:10.17344/acsi.2018.4436

Abstract

In order to determine the structural requirements of fMLP analogs receptors, this work presents the results of a comparative conformational analysis of the active chemotactic peptide (formyl-Met-Leu-Phe-OMe) and its inactive analog (formyl-Met-Leu∆ [CSNH] Phe-OMe) using the theoretical method PEPSEA. This study showed that a ∆ turn structure centered on the central residue is the native structure of the chemotactic peptide fMLP analogs, where both CO(formyl) and NH(central residue) groups are available and ready to interact with the receptor. The inactive analog fMLSP-OMe prefers instead a ∆ turn structure centered on the Met residue, where the two groups cited above are not available for this interaction. Our results and those of literature enable us to propose the "induced fit" model of Burgen for the molecular recognition process. Consequently, the activity of fMLP analogs chemotactic peptides would not be related to a specific secondary structure (∆ turn, ∆ turn or extended….) but rather to the freedom and the availability of the CO(formyl) and the NH group at position 2.

Highlights

The chemotactic peptide fMLP has received much interest in recent years, due to the key role that it plays in our body, in the immune system, it induces the release of the polymorphonuclear leukocytes, the superoxide O–2 and the lysozyme enzyme of the neutrophil.[1,2,3,4] It is considered to be a very active agent.[5]
In order to continue our investigations on the structural requirements of the fMLP chemotactic receptors,[16,24,25] we present, through this work, a comparative conformational study of the parent active peptide and its thioamide analog (formylMet-Leuψ(CSNH)-Phe-OMe) devoid of any activity.[3]
For fMLSP-OMe, the CO(formyl) group acts as H acceptor 30 times: C10 β turns in 9 cases and C7 γ turns in 21 cases

Summary

Introduction

The chemotactic peptide fMLP has received much interest in recent years, due to the key role that it plays in our body, in the immune system, it induces the release of the polymorphonuclear leukocytes, the superoxide O–2 and the lysozyme enzyme of the neutrophil.[1,2,3,4] It is considered to be a very active agent.[5]. The studies carried out by Freidinger et al,[10,11,12,13] which consist to create Lactam bridges in peptide structures and by Perdih et al to synthetis of α-amino-organometallic acids,[14] have shown the success of peptidomimetic in the field of the design of new therapeutic agents. The aim of these modifications is to limit the degrees of freedom and capture the bioactive conformation of a native peptide. The substitution of the formyl group at N-terminal by the tert-butylcarbonyl group (Boc) results in a total loss of activity.[21,22]

Methods

Discussion

Conclusion