Heteroclitic properties of mixed α- and aza-β3-peptides mimicking a supradominant CD4 T cell epitope presented by nucleosome

Dali, Hayet; Busnel, Olivier; Hoebeke, Johan; Bi, Lanrong; Decker, Patrice; Briand, Jean‐Paul; Baudy-Floc'H, M.; Muller, Sylviane

doi:10.1016/j.molimm.2006.12.028

Cited by 24 publications

(37 citation statements)

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“…Aza‐β 3 ‐amino acids are aza derivatives of the β 3 ‐amino acids that bear their side chains on a nitrogen atom with nonfixed configuration increasing the overall conformational flexibility of the backbone, allowing the formation of additional hydrogen bonds and contributing to increased proteolytic resistance (Suplemental Fig. 3) . As peptidomimetics containing aza‐β 3 ‐amino acids were shown to display improved biological profiles and pharmacokinetic properties, we engineered single‐ or double‐substituted aza‐β 3 ‐Mimokines.…”

Section: Resultsmentioning

confidence: 99%

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

Fiévez

Szpakowska

Mosbah

et al. 2018

Journal of Leukocyte Biology

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The chemokine receptor CXCR4 (C-X-C chemokine receptor type 4 also known as fusin or CD184 (cluster of differentiation 184)) is implicated in various biological and pathological processes of the hematopoietic and immune systems. CXCR4 is also one of the major coreceptors for HIV-1 entry into target cells and is overexpressed in many cancers, supporting cell survival, proliferation, and migration. CXCR4 is thus an extremely relevant drug target. Among the different strategies to block CXCR4, chemokine-derived peptide inhibitors hold great therapeutic potential. In this study, we used the N-terminus of vCCL2/vMIPII, a viral CXCR4 antagonist chemokine, as a scaffold motif to engineer and select CXCR4 peptide inhibitors, called Mimokines, which imitate the chemokine-binding mode but display an enhanced receptor affinity, antiviral properties, and receptor selectivity. We first engineered a Mimokine phage displayed library based on the first 21 residues of vCCL2, in which cysteine 11 and 12 were fully randomized and screened it against purified CXCR4 stabilized in liposomes. We identified Mimokines displaying up to 4-fold higher affinity for CXCR4 when compared to the reference peptide and fully protected MT-4 cells against HIV-1 infection. These selected Mimokines were then subjected to dimerization, D-amino acid, and aza-β3-amino acid substitution to further enhance their potency and selectivity. Optimized Mimokines exhibited up to 120-fold enhanced CXCR4 binding (range of 20 nM) and more than 200-fold improved antiviral properties (≤ 1 μM) compared to the parental Mimokines. Interestingly, these optimized Mimokines also showed up to 25-fold weaker affinity for ACKR3/CXCR7 and may therefore serve as lead compounds for further development of more selective CXCR4 peptide inhibitors and probes.

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Section: Resultsmentioning

confidence: 99%

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

Fiévez

Szpakowska

Mosbah

et al. 2018

Journal of Leukocyte Biology

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“…Although we know today that in general a peptide can be loaded in an MHC molecule in a rather short time [68], an intense research has been developed to explore the possibility of replacing natural peptides by pseudopeptides with higher stability for in vivo use [69]. The large family of pseudopeptides includes retro-inverso peptides, which contain NH-CO bonds instead of natural CO-NH bonds, reduced peptide bond pseudopeptides that contain CH2-NH peptide bonds, peptide analogues containing 3 -amino acid residues, and peptides containing aza-3 -amino acid residues, which are oligomers made up of -and aza-3 -amino acid units or Y[CONHNRCH 2 ] [68,[70][71][72][73][74][75][76][77][78][79][80][81][82]. Retro-inverso peptides, reduced peptide bond analogues and mixed -and aza-3 -peptides are remarkably more resistant to proteolysis than are natural peptides [68,70,73,82,83].…”

Section: Scope and Limitations Of Peptides In Therapymentioning

confidence: 99%

“…The large family of pseudopeptides includes retro-inverso peptides, which contain NH-CO bonds instead of natural CO-NH bonds, reduced peptide bond pseudopeptides that contain CH2-NH peptide bonds, peptide analogues containing 3 -amino acid residues, and peptides containing aza-3 -amino acid residues, which are oligomers made up of -and aza-3 -amino acid units or Y[CONHNRCH 2 ] [68,[70][71][72][73][74][75][76][77][78][79][80][81][82]. Retro-inverso peptides, reduced peptide bond analogues and mixed -and aza-3 -peptides are remarkably more resistant to proteolysis than are natural peptides [68,70,73,82,83]. In addition, depending on where the modification is located in the sequence, certain pseudopeptide analogues can be efficiently presented by MHC class I and class II molecules and are recognized in this context by T cell clones and T hybridomas specific for the parent peptide [84][85][86][87][88].…”

Section: Scope and Limitations Of Peptides In Therapymentioning

confidence: 99%

Emerging Peptide Therapeutics for Inflammatory Autoimmune Diseases

Briand

Muller²

2010

CPD

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Current pharmacologic treatments for inflammatory diseases are largely palliative rather than curative. Most of them result in nonspecific immunosuppression. This can be associated with disruption of natural and induced immunity with significant, sometimes dramatic, adverse effects. Among the novel strategies that are under development, tools that target specific molecular pathways and cells, and more precisely modulate the immune system to restore normal tolerance mechanisms are central. In these approaches, peptide therapeutics constitute a valuable class of therapeutic agents. They possess a number of intrinsic properties that are favorable for long-term treatments. They are also versatile components that can be modified to improve their capacities without affecting their bioactivity. Peptide-mediated immunotherapy has been evaluated in several appropriate experimental animal models. A few peptides are currently evaluated in clinical trials for the treatment of human chronic inflammatory diseases. In this review we describe a number of these emerging peptide therapeutics. We also discuss future challenges that, in addition to include selection of appropriate peptide drugs, also involve the optimization of peptide dosage and route of administration as well as the improvement of peptide stability for adequate bioavailability and specific targeting.

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“…First, we developed strategies to synthesize large series of aza‐β 3 ‐amino acids bearing proteogenic or nonproteogenic side chains suitable for straightforward solid‐phase peptide synthesis . Then, we showed that peptides containing aza‐β 3 ‐amino acids can exert various biological activities and we synthesized highly stable AMP mimics with enhanced antimicrobial activities …”

Section: Introductionmentioning

confidence: 99%

Selectivity Modulation and Structure of α/aza‐β³ Cyclic Antimicrobial Peptides

Laurencin

Simon

Fleury

et al. 2018

Chemistry A European J

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Potent and selective antimicrobial cyclic pseudopeptides (ACPPs) mixing α- and aza-β -amino acids were developed. Cyclopseudopeptide sequences were designed to investigate the impact of some intrinsic molecular parameters on their biological activities. Fine changes in the nature of the side chains strongly modulated the selectivity of the ACPPs with regard to hemolysis versus antimicrobial activity. The conformational preference of such compounds in various media was extensively studied, and the typical structure of cyclic α/aza-β -pseudopeptides is described for the first time. Interestingly, such scaffolds are stabilized by successive inverse γ- and N-N turns (hydrazino turns), a unique feature due to the aza-β residues. The α-amino acid side chains form a cluster on one face of the ring, while the aza-β -amino acid side chains are projected around the ring in the equatorial orientation. Such structural data are particularly valuable to fine-tune the bioactivity of these ACPPs by a structure-based approach.

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Heteroclitic properties of mixed α- and aza-β3-peptides mimicking a supradominant CD4 T cell epitope presented by nucleosome

Cited by 24 publications

References 50 publications

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

Emerging Peptide Therapeutics for Inflammatory Autoimmune Diseases

Selectivity Modulation and Structure of α/aza‐β³ Cyclic Antimicrobial Peptides

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Heteroclitic properties of mixed α- and aza-β3-peptides mimicking a supradominant CD4 T cell epitope presented by nucleosome

Cited by 24 publications

References 50 publications

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

Development of Mimokines, chemokine N terminus-based CXCR4 inhibitors optimized by phage display and rational design

Emerging Peptide Therapeutics for Inflammatory Autoimmune Diseases

Selectivity Modulation and Structure of α/aza‐β3 Cyclic Antimicrobial Peptides

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Product

Resources

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Selectivity Modulation and Structure of α/aza‐β³ Cyclic Antimicrobial Peptides