Molecular‐Size Reduction of a Potent CXCR4‐Chemokine Antagonist Using Orthogonal Combination of Conformation‐ and Sequence‐Based Libraries

Abstract

Peptide auf das Wesentliche beschränkt: Das Pentapeptid cyclo(‐L‐Nal 1‐Gly 2‐D‐Tyr 3‐L‐Arg 4‐L‐Arg 5‐) wurde durch Kombination einer konformationsbasierten mit einer sequenzbasierten Peptid‐Bibliothek als möglicher CXCR4‐Antagonist ermittelt (Nal=L‐3‐(2‐Naphthyl)alanin; Bild: Projektion der fünf energetisch günstigsten Strukturen). Mit einem IC50‐Wert von 4 nM ist es vergleichbar effektiv wie die 14‐Aminosäuren‐Stammverbindung T140.

The partial retro–inverso modification: A road traveled together

“…A sequence-based sublibrary of cyclo (-Nal-Gly-Tyr-Arg-Arg-) (8) (the three-letter notation presented in italics indicates undefined chirality) was subjected to a full set of chiral permutations yielded cyclo(-D-Nal-Gly-Tyr-Arg-Arg-) (8K), which was as potent as T140 in inhibiting [ 125 I]-stromal cell-derived factor-1 from binding to CXCR4 receptor and in blocking HIV-induced cytopathogenicity in MT-4 cells (IC 50 ϭ 4 nM and EC 50 ϭ 38 nM, respectively). 78 Performing the same chiral "screen" on the retro sequence cyclo(-Tyr-Gly-Nal-ArgArg-) (10) yielded a RI sublibrary (10A-P) of the previously studied sequence-based sublibrary (8A-P) ( Figure 16B). Interestingly, the "hits" identified in the 10A-P sublibrary were not the RI isomers of the "hits" identified in the 8A-P sublibrary (Fig.…”

“…Arrow indicates the backbone directions. 78,79 antagonist of the CXCR4-chemokinine receptor, a cyclopentapeptide template comprised of the pharmacologically significant residues Arg 2 , Nal 3 , Tyr 5 , and Arg 14 , and Gly as a linker, was subjected to an innovative combinatorial approach ( Figure 16A). 78 The orthogonal combination of a sequence-based library (presenting all possible permutations of 4 chiral residues and a Gly) and a conformation-based library (including all possible permutations of sequences comprised from two Arg residues and one of each, Tyr, Nal, and Gly) will allow an exhaustive exploration of all topochemical relationships in search of a novel small size T140-like cyclic pentapeptide (Figure 16B).…”

“…78,79 antagonist of the CXCR4-chemokinine receptor, a cyclopentapeptide template comprised of the pharmacologically significant residues Arg 2 , Nal 3 , Tyr 5 , and Arg 14 , and Gly as a linker, was subjected to an innovative combinatorial approach ( Figure 16A). 78 The orthogonal combination of a sequence-based library (presenting all possible permutations of 4 chiral residues and a Gly) and a conformation-based library (including all possible permutations of sequences comprised from two Arg residues and one of each, Tyr, Nal, and Gly) will allow an exhaustive exploration of all topochemical relationships in search of a novel small size T140-like cyclic pentapeptide (Figure 16B). A sequence-based sublibrary of cyclo (-Nal-Gly-Tyr-Arg-Arg-) (8) (the three-letter notation presented in italics indicates undefined chirality) was subjected to a full set of chiral permutations yielded cyclo(-D-Nal-Gly-Tyr-Arg-Arg-) (8K), which was as potent as T140 in inhibiting [ 125 I]-stromal cell-derived factor-1 from binding to CXCR4 receptor and in blocking HIV-induced cytopathogenicity in MT-4 cells (IC 50 ϭ 4 nM and EC 50 ϭ 38 nM, respectively).…”

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

“…For the SAR study in position 3, we therefore replaced 2-Nal with aromatic and aliphatic residues of different size and shape, giving a compound series that contained 50 small (4-6), medium (7)(8)(9)(10), and large (11, 12) side chains (Fig. 2).…”

“…1), 9 and eventually to the discovery of the cyclopentapeptide FC131 (2, Fig. 1), 10 which we are currently using as lead compound for our ongoing efforts toward peptidomimetic CXCR4 antagonists. A 16-mer analogue of 1 that contains two additional C-terminal residues (CVX15, 3,…”