Unknown

Dataset Information

0

Covalent Bonding of Pyrrolobenzodiazepines (PBDs) to Terminal Guanine Residues within Duplex and Hairpin DNA Fragments.


ABSTRACT: Pyrrolobenzodiazepines (PBDs) are covalent-binding DNA-interactive agents with growing importance as payloads in Antibody Drug Conjugates (ADCs). Until now, PBDs were thought to covalently bond to C2-NH2 groups of guanines in the DNA-minor groove across a three-base-pair recognition sequence. Using HPLC/MS methodology with designed hairpin and duplex oligonucleotides, we have now demonstrated that the PBD Dimer SJG-136 and the C8-conjugated PBD Monomer GWL-78 can covalently bond to a terminal guanine of DNA, with the PBD skeleton spanning only two base pairs. Control experiments with the non-C8-conjugated anthramycin along with molecular dynamics simulations suggest that the C8-substituent of a PBD Monomer, or one-half of a PBD Dimer, may provide stability for the adduct. This observation highlights the importance of PBD C8-substituents, and also suggests that PBDs may bind to terminal guanines within stretches of DNA in cells, thus representing a potentially novel mechanism of action at the end of DNA strand breaks.

SUBMITTER: Mantaj J 

PROVIDER: S-EPMC4824457 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC5704973 | biostudies-literature
| S-EPMC9774941 | biostudies-literature
| S-EPMC4617767 | biostudies-literature
| S-EPMC7927569 | biostudies-literature
| S-EPMC4706233 | biostudies-literature
| S-EPMC6319256 | biostudies-literature
| S-EPMC5950798 | biostudies-other
| S-EPMC5989393 | biostudies-literature
| S-EPMC5094442 | biostudies-literature
| S-EPMC8162903 | biostudies-literature