Structure–activity relationship studies on CXCR4 antagonists having cyclic pentapeptide scaffolds

Tamamura, Hirokazu; Esaka, Ai; Ogawa, Teppei; Araki, Takanobu; Ueda, Satoshi; Wang, Zixuan; Trent, John O.; Tsutsumi, Hiroshi; Masuno, Hiroyuki; Nakashima, Hideki; Yamamoto, Naoki; Peiper, Stephen C.; Otaka, Akira; Fujii, Nobutaka

doi:10.1039/b513145f

Cited by 34 publications

(55 citation statements)

References 19 publications

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“…In addition to the Ala 3 analogue that was classified as inactive, result in good activity, 14 which could be expected based on the structural similarity with 2-Nal. In contrast, N-methylation (NMe-2-Nal 3 ) was shown to significantly reduce the antagonistic activity, 16 while introduction of a conformationally constrained Trp-derivative resulted in an inactive compound.…”

Section: Design and Sar For Positionmentioning

confidence: 99%

“…21 Similarly, replacement of the 4-hydroxyl group with a 4-amino or a 4-methoxy group resulted in 13-fold and 64-fold reduction in affinity, respectively. 14 Overall, the reported phenyl- 14 (Fig. 3).…”

Section: Design and Sar For Positionmentioning

confidence: 99%

“…4A). The restrictions of this subpocket would explain the reduced potency (14); the 4-hydroxyl group of 2 forms an additional H-bond with Glu32 (Fig. 4B), which would explain its higher activity.…”

Section: Rationalization Of Sar For the Two Aromatic Positions In Termentioning

confidence: 99%

“…14,16,20,21 The L- analogue resulted in a 6-fold reduction in affinity, 14 while introduction of a halogen on the phenyl ring led to further affinity reduction. 21 Similarly, replacement of the 4-hydroxyl group with a 4-amino or a 4-methoxy group resulted in 13-fold and 64-fold reduction in affinity, respectively.…”

Section: Design and Sar For Positionmentioning

confidence: 99%

“…2). For reference purposes the known Ala 3 analogue 13 14 was also included. Our synthetic strategy for preparation of cyclopentapeptide ligands and the biological assay for determination of antagonistic potency have recently been 55 described.…”

Section: Design and Sar For Positionmentioning

confidence: 99%

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Structure–activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

et al. 2013

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The cyclopentapeptide CXCR4 antagonist FC131 (cyclo(-Arg 1 -Arg 2 -2-Nal 3 -Gly 4 -D-Tyr 5 -), 2; 2-Nal = 3-(2-naphthyl)alanine) represents an excellent starting point for development of novel drug-like ligands with therapeutic potential in HIV, cancer, stem-cell mobilization, inflammation, and autoimmune diseases. While the structure-activity relationships for Arg 1 , Arg 2 , and Gly 4 are well established, less is 10 understood about the roles of the aromatic residues 2-Nal 3 and D-Tyr 5 . Here we report further structureactivity relationship studies of these two positions, which showed that (i) the distal aromatic ring of the 2-Nal 3 side chain is required in order to maintain high potency, and (ii) replacement of D-Tyr 5 with conformationally constrained analogues results in significantly reduced activity. However, a simplified analogue that contained Gly instead of D-Tyr 5 was only 13-fold less potent than 2, which means that the 15 D-Tyr 5 side chain is dispensable. These findings were rationalized based on molecular docking, and the collective structure-activity data for the cyclopentapeptides suggest that appropriately designed Arg 2 -2-Nal 3 dipeptidomimetics have potential as CXCR4 antagonists.

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Section: Design and Sar For Positionmentioning

confidence: 99%

Section: Design and Sar For Positionmentioning

confidence: 99%

Section: Rationalization Of Sar For the Two Aromatic Positions In Termentioning

confidence: 99%

Section: Design and Sar For Positionmentioning

confidence: 99%

Section: Design and Sar For Positionmentioning

confidence: 99%

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Structure–activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

et al. 2013

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Computational Approaches in Peptide and Protein Design: An Overview

Nikiforovich¹,

Marshall

2009

Peptide and Protein Design for Biopharmaceutical Applications

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A minimalistic 3D pharmacophore model for cyclopentapeptide CXCR4 antagonists

2006

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Because of its involvement in HIV entry, the chemokine receptor CXCR4 is an attractive target for antiretroviral drugs. Despite the large number of CXCR4 inhibitors studied, the 3D pharmacophore for binding to CXCR4 remains elusive, mainly as a result of conformational flexibility inherent in the identified ligands. In the present study, an exhaustive systematic exploration of the conformational space for a series of analogs of FC131, a cyclopentapeptide CXCR4 antagonist, has been performed. By comparing the resulting low-energy conformations using different sets of atoms, specific conformational features common only to the high/medium affinity compounds were identified. These features included the spatial arrangement of three pharmacophoric side chains as well as the orientation of a specific backbone amide bond. Together these features represent a minimalistic 3D pharmacophore model for binding of the cyclopentapeptide antagonists to CXCR4. The model enables rationalization of the experimental affinity data for this class of compounds as well as for the peptidomimetic KRH-1636.

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Structure–activity relationship studies on CXCR4 antagonists having cyclic pentapeptide scaffolds

Cited by 34 publications

References 19 publications

Structure–activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

Structure–activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

Computational Approaches in Peptide and Protein Design: An Overview

A minimalistic 3D pharmacophore model for cyclopentapeptide CXCR4 antagonists

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