Rational Design of Conformationally Constrained Cyclopentapeptide Antagonists for C-X-C Chemokine Receptor 4 (CXCR4)

Mungalpara, Jignesh; Thiele, Stefanie; Eriksen, Øystein; Eksteen, Jacobus Johannes; Våbenø, Jon

doi:10.1021/jm300926y

Cited by 25 publications

(40 citation statements)

References 30 publications

(86 reference statements)

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“…Extensive SAR studies of FC131 involving more conservative side chain modifications have been performed, and due to the large number of analogs, we only summarize the main findings. § Arg 1 is relatively tolerant to a range of structural modifications, indicating that it participates in non--specific receptor interactions [88,96,97]. § Arg 2 is very sensitive to the same modifications, indicating that it is involved in highly specific receptor interactions [97,98].…”

Section: Side Chain Modificationsmentioning

confidence: 99%

“…§ Arg 1 is relatively tolerant to a range of structural modifications, indicating that it participates in non--specific receptor interactions [88,96,97]. § Arg 2 is very sensitive to the same modifications, indicating that it is involved in highly specific receptor interactions [97,98]. § 2--Nal 3 is also sensitive to modifications, and the distal aromatic ring has been shown to be especially important [98,99].…”

Section: Side Chain Modificationsmentioning

confidence: 99%

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Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

Våbenø

Haug

2015

Future Med. Chem.

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Over the last five years, X--ray structures of CXC chemokine receptor 4 (CXCR4) in complex with three different ligands (the small--molecule antagonist IT1t, the polypeptide antagonist CVX15, and the viral chemokine antagonist vMIP--II) have been released. In addition to the inherent scientific value of these specific X--ray structures, they (i) provide a reliable structural foundation for studies of the molecular interactions between CXCR4 and its key peptide ligands (CXCL12 and HIV--1 gp120); and (ii) serve as valuable templates for further development of small--molecule CXCR4 antagonists with therapeutic potential. We here review recent computational studies of the molecular interactions between CXCR4 and its peptide ligands -based on the X--ray structures of CXCR4 -and the current status of small--molecule peptide and peptidomimetic CXCR4 antagonists. 2) Isostere: In the context of this review, an isostere is defined as any functional group or moiety that is included in a peptide sequence as a replacement of an amide bond.3) Scaffold: The term scaffold is used for rigid (normally cyclic) structures onto which the functional groups of amino acid side chains can be introduced. 4) Structure--based and ligand--based design:In structure--based design, the 3D structure of the target is known and guides the design of active compounds. When the 3D structure of the target is unknown, indirect information has to be used in order to design/optimize compounds that bind to the target. This information is normally obtained through SAR studies and pharmacophore modeling, and the overall approach is known as ligand--based design. 5) 7TM receptors: As signalling via G proteins is a common feature for seven--

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Section: Side Chain Modificationsmentioning

confidence: 99%

Section: Side Chain Modificationsmentioning

confidence: 99%

Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

Våbenø

Haug

2015

Future Med. Chem.

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“…As SAR studies of the cyclopentapeptide CXCR4 antagonists (Figure 1) have demonstrated that position 2 (L-Arg) is very sensitive to structural modifications, 12,13 we decided to keep LArg 2 throughout this study. Similarly, we have recently shown that replacement of L-2-Nal in position 3 with aromatic/alicyclic analogs results in significant reduction of the antagonistic potency, 11 and therefore used a 2-naphthyl group with the appropriate spacer length for all compounds.…”

Section: General Design Considerationsmentioning

confidence: 99%

“…The antagonistic potency of the synthesized compounds 2-14 ( Figures 2 and 6) on human CXCR4 was determined by a functional assay as previously described 13 and is shown in Table 1; the EC 50 -value of the known lead compound 2 was 0.52 µM. …”

Section: Biological Evaluationmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of scaffold-based tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

Zachariassen

Thiele

Berg

et al. 2014

Bioorganic & Medicinal Chemistry

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Structure-activity relationship studies of the cyclopentapeptide CXCR4 antagonists (cyclo(-L-sequence contained within these cyclopentapeptides serves as a recognition motif for peptidic CXCR4 antagonists. Starting by dissecting the cyclopentapeptide structure and reintroducing cyclic constraints in a stepwise manner, we here report a novel class of scaffold-based tripeptidomimetic CXCR4 antagonists based on the D-Arg-Arg-2-Nal motif. Biological testing of the prototype compounds showed that they represent new peptidomimetic hits;importantly, the modular nature of the scaffold provides an interesting starting point for future ligand optimization. Graphical Abstract Cyclopentapeptide

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Disulfide Bond Replacement with 1,4‐ and 1,5‐Disubstituted [1,2,3]‐Triazole on C‐X‐C Chemokine Receptor Type 4 (CXCR4) Peptide Ligands: Small Changes that Make Big Differences

Tomassi

Trotta

Ieranò

et al. 2020

Chemistry A European J

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Here we investigated the structurala nd biological effects ensuing from the disulfide bond replacement of a potent and selective C-X-C chemokine receptor type 4 (CXCR4) peptide antagonist, with 1,4-and 1,5-disubstituted 1,2,3-triazole moieties. Both strategies produced candidates that showedh igh affinity and selectivity against CXCR4. Notably,w hen assessed for their ability to modulate the CXCL12-mediated cell migration, the 1,4-triazole variant conserved the antagonistic effect in the low-mid nanomolar range, while the 1,5-triazole one displayed the ability to activate the migration, becoming the first in class low-molecular-weight CXCR4 peptide agonist. By combining NMR and computational studies, we provided av aluablem odel that highlighted differences in the interactions of the two peptidomimeticsw ith the receptor that could accountf or their different functional profile. Finally, we envisage that our findings could be translated to different GPCR-interacting peptides for the pursuit of novel chemical probes that could assist in dissecting the complex puzzle of this fundamental class of transmembrane receptors.

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Rational Design of Conformationally Constrained Cyclopentapeptide Antagonists for C-X-C Chemokine Receptor 4 (CXCR4)

Cited by 25 publications

References 30 publications

Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

Design, synthesis, and biological evaluation of scaffold-based tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

Disulfide Bond Replacement with 1,4‐ and 1,5‐Disubstituted [1,2,3]‐Triazole on C‐X‐C Chemokine Receptor Type 4 (CXCR4) Peptide Ligands: Small Changes that Make Big Differences

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