Abstract
Bleomycins are antitumor antibiotics that can chelate a metal center and cause site-specific DNA cleavage at 5'-Gpyrimidine-3' regions of DNA. These antibiotics are successful in the treatment of various cancers, but are known to cause pulmonary fibrosis to patients under bleomycin regimes. Substantial research has resulted in the development of over 300 bleomycin analogs, aiming to improve the therapeutic index of the drug. Previous studies have proposed that the lung toxicity caused by bleomycin is related to the C-terminal regions of these drugs, which have been shown to closely interact with DNA in metal-bleomycin-DNA complexes. Some of the research studying metallo-bleomycin-DNA interactions have suggested three different binding modes of the metal form of the drug to DNA, including total and/or partial intercalation, and minor groove binding. However, there is still lack of consensus regarding this matter, and solid conclusions on the subject have not yet been established. Previously we investigated the diverse levels of disruption caused to DNA hairpins containing 5'-GC-3' and 5'-GT-3' binding sites, which are consequence of the binding of bleomycins with different C-termini. The results of these investigation indicate that both the DNA-binding site and the bleomycin C-termini have an impact on the final conformations of drug and target. The present study focuses on the structural alterations exhibited by Zn(II)bleomycin-A2, -B2, -A5 and Zn(II)peplomycin upon binding to DNA hairpins containing 5'-GC-3' and 5'-GT-3' binding sites. Evidence that each Zn(II)bleomycin is structurally affected depending on both its C-terminus and the DNA-binding site present in the hairpin is provided.
Highlights
Bleomycins (BLMs) compose a family of glycopeptide-derived antibiotics produced by Streptomyces verticillus [1]
The 1H-NMR signals elicited by free Zn(II)BLM-A2, -A5, -B2, and Zn(II)PEP were assigned using correlation spectroscopy (COSY), totally correlated spectroscopy (TOCSY), and nuclear Overhauser effect spectroscopy (NOESY) spectra acquired in H2O at 5 ◦C
The NOESY spectra of these Zn(II)BLMs bound to OL1 and OL2 (Supplementary Figures S1–S4) acquired in H2O at 5 ◦C previously examined [50,51] were analyzed this time to identify the signals generated by the bound Zn(II)BLMs, and investigate the effects that OL complexation has on the conformation of each Zn(II)BLMs
Summary
Bleomycins (BLMs) compose a family of glycopeptide-derived antibiotics produced by Streptomyces verticillus [1]. The overall structure of these agents can be thought of as containing four distinct regions (Figure 1): the metal binding domain (D1), which is responsible for metal binding [5,6], oxygen activation [5,7,8,9], and site-selective DNA cleavage [6,10]; the peptide linker (D2); the DNA binding domain (D3), containing a bithiazole moiety and the C-terminus, which provides the majority of the DNA binding affinity [11,12]; and the disaccharide moiety (D4), which influences metal ion binding [6,13,14,15,16,17,18,19,20,21,22,23,24] and is proposed to be a tumor-targeting unit [25]. SLoMmestoruf cthtueraev, afiolcaublseinsgtuadlimesohstaveexcblruiseiflvyeleyxaomn intheed bthitehiinazflouleen(cBeitD) NanAdhtahseonβthheydMroBxLyMhissttirduicnteur(eH, fiostc)umsinogieatilems oisnt eBxLcMlus[i3v5e,l3y6o–3n9t,h47e,b48it]h. iAazdodleit(ioBnita)lalyn,dththeeBβL-hMysdruosxeydhiisntidthinesee (Hstuisdt)iems aorieetliiems iitnedB, LwMith[t3h5e–3m9,a4jo7,r4it8y].usAindgdMitiBoLnaMll-yA, 2th[3e5,B3L6–M43s,4u7s]e,danidn stohmeseeinstvuedstieigsaatirneglMimBitLeMd,with the majority using MBLM-A2 [35,36,37,38,39,40,41,42,43,47], and some investigating MBLM-A5 [37], MBLM-B2 [46]
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