Computational modeling and experimental validation of the EPI-X4/CXCR4 complex allows rational design of small peptide antagonists

Sokkar, Pandian; Harms, Mirja; Stürzel, Christina M.; Gilg, Andrea; Kızılsavaş, Gönül; Raasholm, Martina; Preising, Nico; Wagner, Manfred; Kirchhoff, Frank; Ständker, Ludger; Weidinger, Gilbert; Mayer, Benjamin; Münch, Jan; Sánchez-García, Elsa

doi:10.1038/s42003-021-02638-5

Cited by 24 publications

(65 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The structures of the complexes, formed by CXCR4 and each peptide mutant, were generated via homology modeling using as a template the structural model of the complex CXCR4/EPI-X4, reported by Sokkar et al. , We estimated the BA of each complex with different predictors, as well as the associated enrichment factors.…”

Section: Resultsmentioning

confidence: 99%

PPI-Affinity: A Web Tool for the Prediction and Optimization of Protein–Peptide and Protein–Protein Binding Affinity

et al. 2022

Self Cite

View full text Add to dashboard Cite

Virtual screening of protein–protein and protein–peptide interactions is a challenging task that directly impacts the processes of hit identification and hit-to-lead optimization in drug design projects involving peptide-based pharmaceuticals. Although several screening tools designed to predict the binding affinity of protein–protein complexes have been proposed, methods specifically developed to predict protein–peptide binding affinity are comparatively scarce. Frequently, predictors trained to score the affinity of small molecules are used for peptides indistinctively, despite the larger complexity and heterogeneity of interactions rendered by peptide binders. To address this issue, we introduce PPI-Affinity, a tool that leverages support vector machine (SVM) predictors of binding affinity to screen datasets of protein–protein and protein–peptide complexes, as well as to generate and rank mutants of a given structure. The performance of the SVM models was assessed on four benchmark datasets, which include protein–protein and protein–peptide binding affinity data. In addition, we evaluated our model on a set of mutants of EPI-X4, an endogenous peptide inhibitor of the chemokine receptor CXCR4, and on complexes of the serine proteases HTRA1 and HTRA3 with peptides. PPI-Affinity is freely accessible at .

show abstract

Section: Resultsmentioning

confidence: 99%

PPI-Affinity: A Web Tool for the Prediction and Optimization of Protein–Peptide and Protein–Protein Binding Affinity

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…The 12-mer peptide EPI-X4 JM#21 used in this work is an optimized derivative of the endogenous peptide CXCR4 inhibitor EPI-X4 with the sequence ILRWSRKLP C VS (Figure C), which showed promising therapeutic effects in mouse models of CXCR4-associated diseases, such as atopical dermatitis, asthma, and Waldenström’s Macroglobulinemia. , EPI-X4 JM#21 has a native thiol group (Cys-10) that is not featured in the pharmacophore for target binding , and therefore can be used for bioconjugation. We minimized variability between conjugates by establishing two bioconjugation methods that suited all carriers used in this work.…”

Section: Resultsmentioning

confidence: 99%

“…(A) Conformational clusters of the JM#21 peptide. The trajectory of the monomeric CXCR4-JM#21 complex was superposed onto each monomer of the CXCR4 dimer (PDB ID 3ODU, ref ). Red: JM#21 conformations where the two Cys10 residues are close enough to be bridged by the bis-sulfone linker.…”

Section: Resultsmentioning

confidence: 99%

“…The key structural element for the four most potent, Y-shaped conjugates was the peptide dimerization via a short spacer between the two peptide copies. Our hypothesis is that the observed structure–activity relationship is due to the ability of the Y-shaped conjugates to bind to two CXCR4 molecules at the same time. , CXCR4 is well known for its tendency to dimerize, especially on cells with a high receptor expression, for example, cancer cells. ,− On the one hand, divalent binding of the conjugate may be expected to stabilize the CXCR4 dimer; on the other hand, divalent binding is often characterized by enhanced potency. − To gain an initial computational insight into the possibility of such a divalent binding, we used the previously reported structural model of JM#21 bound to a monomeric CXCR4 (ref ). According to this computational model, the peptide binds to the receptor binding pocket via its N-terminus.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Dimerization of the Peptide CXCR4-Antagonist on Macromolecular and Supramolecular Protraction Arms Affords Increased Potency and Enhanced Plasma Stability

et al. 2022

Self Cite

View full text Add to dashboard Cite

Peptides are prime drug candidates due to their high specificity of action but are disadvantaged by low proteolytic stability. Here, we focus on the development of stabilized analogues of EPI-X4, an endogenous peptide antagonist of CXCR4. We synthesized macromolecular peptide conjugates and performed side-by-side comparison with their albumin-binding counterparts and considered monovalent conjugates, divalent telechelic conjugates, and Y-shaped peptide dimers. All constructs were tested for competition with the CXCR4 antibody−receptor engagement, inhibition of receptor activation, and inhibition of the CXCR4tropic human immunodeficiency virus infection. We found that the Y-shaped conjugates were more potent than the parent peptide and at the same time more stable in human plasma, with a favorable outlook for translational studies.

show abstract

“…At last, EPI-X4, a natural fragment of albumin and EPI-X4 derived peptides have been shown to inhibit inflammatory cell infiltration in a mouse model of allergic hypereosinophilia [ 43 ] and reduce skin inflammation in a mouse model of atopic dermatitis [ 44 ]. Moreover, these peptides share key interactions at CXCR4 with IT1t [ 45 ].…”

Section: Cxcr4 As Target For Inflammationmentioning

confidence: 99%

CXCR4 as a novel target in immunology: moving away from typical antagonists

Caspar

Cocchiara

Melet

et al. 2022

Future Drug. Discov.

View full text Add to dashboard Cite

CXCR4 has been a target of interest in drug discovery for numerous years. However, so far, most if not all studies focused on finding antagonists of CXCR4 function. Recent studies demonstrate that targeting a minor allosteric pocket of CXCR4 induces an immunomodulating effect in immune cells expressing CXCR4, connected to the TLR pathway. Compounds binding in this minor pocket seem to be functionally selective with inverse agonistic properties in selected GPCR signaling pathways (Gi activation), but additional signaling pathways are likely to be involved in the immunomodulating effects. In depth research into these CXCR4-targeted immunomodulators could lead to novel treatment options for (auto)-immune diseases.

show abstract

Computational modeling and experimental validation of the EPI-X4/CXCR4 complex allows rational design of small peptide antagonists

Cited by 24 publications

References 46 publications

PPI-Affinity: A Web Tool for the Prediction and Optimization of Protein–Peptide and Protein–Protein Binding Affinity

PPI-Affinity: A Web Tool for the Prediction and Optimization of Protein–Peptide and Protein–Protein Binding Affinity

Dimerization of the Peptide CXCR4-Antagonist on Macromolecular and Supramolecular Protraction Arms Affords Increased Potency and Enhanced Plasma Stability

CXCR4 as a novel target in immunology: moving away from typical antagonists

Contact Info

Product

Resources

About