NEWS
2011 - 09 - 12 Original review from Dr Andy Chevigné, Laboratory of Retrovirology
Nowadays 33.3 million people were living with HIV. The chemokine receptor CXCR4 is the principal co-receptors used by HIV-1 viruses infecting T- cells and responsible for the onset of AIDS. In addition, CXCR4 plays a prominent role in cancer and tumor biology. In this regard, the development of CXCR4 antagonists holds promising therapeutic applications in the field of HIV and cancer.
In January 2011, the Laboratory of Retrovirology presented a poster entitled ” Development of MIMOKINES, a New Class of Short CXCR4 Antagonists for Cancer and HIV-1 Treatment” at the Cells SignalOmics Congress, organized in Luxembourg by Dr. Marc Diederich from the LBMCC.
Following this poster presentation, the Journal of Biochemical Pharmacology invited Dr. Andy Chevigné, to publish a review focused on the engineering and screening of the N-terminus of chemokines for drug discovery. Thanks to the collaboration of Dr. Virginie Fievez, Dr. Jean-Claude Schmit and Dr. Sabrina Deroo first results related to the FNR CORE project “Development of Mimokines, a new Class of Short CXCR4 Antagonists Mimicking Natural Chemokine” managed by Dr. Andy Chevigné have been described.
Earlier this year Dr Chevigné and his team published a first paper on the identification of CXCR4 antagonists using antibody fragments in The FEBS Journal. A complementary route to chemokine engineering was followed and resulted in the identification of at least one CXCR4 antagonist derived from the HCDR3 sequence of human antibodies
Besides the mimokines project, Dr. Chevigné is leading the project entitled “Exploring the structural and functional surface of CXCR4 and CXCR7 receptors” as Project Investigator.
He will be one of the key speakers at the “Second International Workshop on protein expression and purification strategies which will be held at Chulalongkorn, in Bangkok, Thailand on October 2011. Dr Chevigné will give a lecture entitled "Phage display technology for protein engineering and protein molecular recognition".
Read the abstracts:
Abstract 1:
Chemokines are small chemoattractive proteins involved in many important physiological and pathological processes such as leukocyte mobilisation, inflammation, cancer and HIV-1 infection. The N-terminus of chemokines was shown to be crucial for interaction and activation with their cognate receptors. Therefore, multiple strategies including elongation, truncation, mutagenesis or chemical modifications of chemokine N-terminus were developed to identify analogues with modified selectivity displaying antagonist or enhanced agonist activities. Library approaches allowed fast screening of a large number of such chemokine variants and led to the identification of promising therapeutic candidates.
Additional studies were able to reduce the chemokine to the size of a peptide while retaining its receptor affinity and selectivity. In analogy to full length chemokines, peptides derived from the chemokine N-terminal sequence were improved by mutagenesis, elongation and truncation approaches to develop potential therapeutic molecules used in various clinical trials.
Altogether these studies demonstrated the pharmacophore potential of the chemokine N-terminus and its vast modulation properties to develop analogues with great therapeutic value for a large set of pathologies.
Abstract 2:
Phage display technology is a powerful selection approach to identify strong and specific binders to a large variety of targets. In this study, we compared the efficacy of a phage library displaying human 3 (HCDR3) repertoires heavy chain complementarity determining region with a set of conventional random peptide libraries for the identification of CXCR4 antagonists using a peptide corresponding to the second extracellular loop of the receptor CXCR4 as target. A total of 11 selection campaigns on this target did not result in any specific ligand from the random peptide libraries. In contrast, a single selection campaign with an HCDR3 library derived from the IgM repertoire of a nonimmunized donor resulted in nine specific peptides with lengths ranging from 10 to 19 residues. Four of these HCDR3 sequences interacted with native receptor and the most frequently isolated peptide μm and acted as a CXCR4 antagonist (IC(50) displayed an affinity of 5.6 μm). To comprehend the basis of the highly efficient HCDR3 23 = library selection, its biochemical properties were investigated. The HCDR3 length varied from 3 to 21 residues and displayed a biased amino acid content with a predominant proportion of Tyr, Gly, Ser and Asp. Repetitive and conserved motifs were observed in the majority of the HCDR3 sequences. The strength and efficacy of the HCDR3 libraries reside in the combination of multiple size peptides and a naturally biased sequence variation. Therefore, HCDR3 libraries represent a powerful and versatile alternative to fully randomized peptide libraries, in particular for difficult targets.
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