Shape-selective recognition of a model Okazaki fragment by geometrically-constrained bis-distamycins.
Okazaki fragments represent interesting targets for the design of anticancer drugs because of their selective occurrence during DNA replication, a process often elevated in aggressive malignancies. Structural studies have indicated a bend occurs in the helical axis at the junction region (JR) that joins the DNA duplex region (DDR) and the RNA-DNA hybrid duplex region (HDR) of model Okazaki fragments. To identify a structural motif that provides a shape complementary to the Okazaki fragment minor groove, we have investigated the binding of geometrically-constrained bis-distamycins to a model Okazaki fragment, [OKA], with a sequence derived from the genome of simian virus 40 (SV40). Both the JR and the DDR of [OKA] contain consecutive A/T base pairs that could accommodate distamycin binding. Of the six bis-distamycins selected for analysis, the two with a para configuration of the distamycins on the benzene or pyridine scaffold bound [OKA] tightly (Kd approximately 10(-6) M from gel-shift assays; Kd approximately 10(-8) M from deltaT(M)) while the four with a meta orientation did not bind. The two mono-distamycins studied also did not bind [OKA]. Molecular modeling of the complex between the para bis-distamycin MT-9 and [OKA] revealed MT-9 adopted an S- shape complementary to the minor groove of the model Okazaki fragment.
Gmeiner
W H
WH
Eppley Institute, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198-6805, USA. bgmeiner@unmc.edu
Cui
W
W
Konerding
D E
DE
Keifer
P A
PA
Sharma
S K
SK
Soto
A M
AM
Marky
L A
LA
Lown
J W
JW
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D004261:DNA Replication; D004279:DNA, Viral / Q000737:chemistry*; D004214:Distamycins / Q000737:chemistry*; D015195:Drug Design; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D013539:Simian virus 40 / Q000235:genetics
D000970:Antineoplastic Agents; D004279:DNA, Viral; D004214:Distamycins; C022262:Okazaki fragments; D004247:DNA