Theoretical design of a bistetrapeptide derivative of mitoxantrone targeted towards the double-stranded hexanucleotide sequence d(GGCGCC)2.
The hexanucleotide d(GGCGCC)2 is encountered in recurrent fashion within transcriptional activating sequences in retroviruses and protooncogenes. Our first theoretical design of novel oligopeptide derivatives of mitoxantrone, MTX (1), had enabled us to predict derivatives depsiGly-Lys(L) and depsiGly-Gly-Orn(D) to preferentially target the tetrameric core d(CCGG)2. Owing to the crucial importance of hexamer d(GGCGCC)2, we have attempted to extend the realm of our approach by now targeting this specific hexanucleotide. For that purpose, we undertook the design of further oligopeptide derivatives of MTX, in which each arm was identically amidated (rather than esterified as in (1)) by tri- or tetrapeptides of varying sequences and individual residue configurations. The binding affinities of these derivatives to the palindromic sequences d(GGCGCC)2, d(CGCGCG)2, d(GCCGGC)2 and d(CCCGGG)2, were compared by energy-minimization. We report here the results obtained with the most promising derivative, having the sequence Arg(L)-Gly-Val(L)-Glu(L), and displaying a considerable energy preference for d(GGCGCC)2 over the other candidate hexameric sites (referred to as I). In the corresponding complexes, the two arms are in two mutually antiparallel directions in the major groove, and adopt a beta-sheet like arrangement stabilized by two H-bonds involving the carbonyl and amide groups of the Gly residues. Each Arg side chain on a given arm chelates O6 and N7 atoms of G1, G2/G1', G2' with its imino and cis amino hydrogen, and is simultaneously bound through two amino hydrogens in a bidentate interaction with the Glu residue.
Gresh
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Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, Paris, France.
Kahn
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PH
D000595:Amino Acid Sequence; D001482:Base Composition; D001483:Base Sequence; D015195:Drug Design; D008942:Mitoxantrone / Q000031:analogs & derivatives / Q000737:chemistry*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D011485:Protein Binding
D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; D010710:Phosphates; D008942:Mitoxantrone