Target Practice: Aiming at Satellite Repeats with DNA Minor Groove Binders

Abstract

Much progress has been made in recent years in developing small molecules that target the minor groove of DNA. Striking advances have led to the design of synthetic molecules that recognize specific DNA sequences with affinities comparable to those of eukaryotic transcription factors. This makes it feasible to modulate or inhibit DNA/protein interactions in vivo, a major step towards the development of general strategies of anti-gene therapy. Examples from anti-parasitic drugs also suggest that synthetic molecules can affect a variety of cellular functions crucial to cell viability by more generally targeting vast portions of genomes based on their biased base composition. This provides a rationale for developing approaches based on selective interactions with broad genomic targets such as satellite repeats that are associated with structural or architectural components of chromatin essential for cellular proliferation. Using examples drawn from the Drosophila melanogaster model system, we review here the use of synthetic polyamides or diamidines that bind the DNA minor groove and can be used as highly selective agents capable of interfering with specific protein/DNA interactions that occur in A+T-rich repeated sequences that constitute a significant portion of eukaryotic genomes. The satellite localization of cellular proteins that bind the minor groove of DNA via domains such as the AT hook motif is highly sensitive to these molecules. A major consequence of the competition between these proteins and their synthetic mimics is an alteration of the nuclear localization and function of proteins such as topoisomerase II, a major target of anti-cancer drugs.

Lurbinectedin (PM01183), a New DNA Minor Groove Binder, Inhibits Growth of Orthotopic Primary Graft of Cisplatin-Resistant Epithelial Ovarian Cancer

“…The DNA major groove is a site of attack for cisplatin and many alkylating agents, and when cisplatin binds to DNA 3 types of lesions can be formed on purine bases: monoadducts, and intra-and interstrand crosslinks. On the other hand, other antitumor drugs including mitomycin C, chromomycin A 3 , and ecteinascidins, bind to the minor groove (18). One of the best examples is trabectedin (Yondelis), which reacts with certain guanines in the minor groove of DNA to form a covalent bond (19)(20)(21).…”

Design of DNA Minor Groove Binding Diamidines That Recognize GC Base Pair Sequences: A Dimeric-Hinge Interaction Motif

“…Defining new nucleic acid targets is thus a very promising route for expanding useful drug design approaches. Diamidines have excellent transport properties into a variety of cells [3][4][5][6] and an orally available prodrug of the diamidine, DB75, furamidine (Figure 1), is currently in phase III clinical trials against trypanosomes, which cause sleeping sickness, as well as other microbial parasites. 4,[7][8][9][10][11] DB75 binds strongly in the minor groove of DNA and recognizes sequences of at least four AT base pairs.…”

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

“…Aromatic diamidines (AD) and analogues target the minor groove of DNA and represent a promising class of antiparasitic agents (58,65,72). AD and their congeners present broadspectrum activity against pathogenic microorganisms, and some of them have veterinary and human clinical uses {e.g., pentamidine isethionate [1,5-bis(4-amidino-phenoxy)pentane] (Pentacarinat; Rhodia)} (45,57,72).…”