Abstract
There is a long history for the bioorganic and biomedical use of N-methyl-pyrrole-derived polyamides (PAs) that are higher homologs of natural products such as distamycin A and netropsin. This work has been pursued by many groups, with the Dervan and Sugiyama groups responsible for many breakthroughs. We have studied PAs since about 1999, partly in industry and partly in academia. Early in this program, we reported methods to control cellular uptake of polyamides in cancer cell lines and other cells likely to have multidrug resistance efflux pumps induced. We went on to discover antiviral polyamides active against HPV31, where SAR showed that a minimum binding size of about 10 bp of DNA was necessary for activity. Subsequently we discovered polyamides active against two additional high-risk HPVs, HPV16 and 18, a subset of which showed broad spectrum activity against HPV16, 18 and 31. Aspects of our results presented here are incompatible with reported DNA recognition rules. For example, molecules with the same cognate DNA recognition properties varied from active to inactive against HPVs. We have since pursued the mechanism of action of antiviral polyamides, and polyamides in general, with collaborators at NanoVir, the University of Missouri-St. Louis, and Georgia State University. We describe dramatic consequences of β-alanine positioning even in relatively small, 8-ring polyamides; these results contrast sharply with prior reports. This paper was originally presented by JKB as a Keynote Lecture in the 2nd International Conference on Medicinal Chemistry and Computer Aided Drug Design Conference in Las Vegas, NV, October 2013.
Highlights
IntroductionPolyamides (PAs) that recognize and bind the minor groove of DNA have been studied extensively by a number of groups, including those of Dervan [1,2,3], Sugiyama [4,5,6,7], Lee [8,9,10,11], Laemmli [12,13,14], Kodadek [15,16] and others [17,18,19]
Please note that with over 100 PA compounds tested against HPV16, 18 and 31, we have not seen any advantage or systematic effect of using the chiral γ turn (R)2,4-diaminobutyric acid, abbreviated as γ(NH2), in place of γ itself, even though the chiral reagent is reported to impart numerous beneficial properties on shorter PAs [72]
In the case of amine tails Ta and Dp, we have found better antiHPV activity for Ta analogs much of the time, but there are a number of cases where the Dp analog is more active than its Ta counterpart, so there is no systematic preference for one amino tail over the other
Summary
Polyamides (PAs) that recognize and bind the minor groove of DNA have been studied extensively by a number of groups, including those of Dervan [1,2,3], Sugiyama [4,5,6,7], Lee [8,9,10,11], Laemmli [12,13,14], Kodadek [15,16] and others [17,18,19]. One project involved design of polyamides to repress cyclooxygenase-2 (COX-2) gene expression by targeting the binding site of ETS (E26 transformation specific) transcription control superfamily member Ets-1 in the COX-2 promoter, followed by study of the detailed thermodynamics of interactions between active PAs and their Ets-1 target [37]. Another project discovered, and is developing, antiviral agents for high-risk, cancer-causing Human Papillomavirus (HPV), and encompasses understanding the mechanism of action of these antiviral compounds [36,38,41]. We found excellent antiviral efficacy in human cell and tissue culture with compounds exceeding MW of 3000 [36,38,41], and note that Sugiyama and colleagues have reported no difference in cellular uptake of polyamides from 400-4000 in MW, as long as Im content was kept constant [44]
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