Abstract
BackgroundThere is great interest in the design of small molecules that selectively target minor grooves of duplex DNA for controlling specific gene expression implicated in a disease. The design of chiral small molecules for rational drug design has attracted increasing attention due to the chirality of DNA. Yet, there is limited research on the chirality effect of minor groove binders on DNA interaction, especially at the protein expression level. This paper is an attempt to illustrate that DNA binding affinity might not provide a full picture on the biological activities. Drug interacting at the genomic level can be translated to the proteomic level. Here we have illustrated that although the chiral bispyrrole-pyrrolidine-oligoamides, PySSPy and PyRSPy, showed low binding affinity to DNA, their influence at the proteomic level is significant. More importantly, the chirality also plays a role. Two-dimensional proteomic profile to identify the differentially expressed protein in Escherichia coli DH5α (E coli DH5α) were investigated.ResultsE coli DH5α incubated with the chiral PySSPy and PyRSPy, diastereomeric at the pyrrolidine ring, showed differential expression of eighteen proteins as observed through two dimensional proteomic profiling. These eighteen proteins identified by MALDI_TOF/TOF MS include antioxidant defense, DNA protection, protein synthesis, chaperone, and stress response proteins. No statistically significant toxicity was observed at the tested drug concentrations as measured via MTT assay.ConclusionThe current results showed that the chiral PySSPy and PyRSPy impact on the proteomic profiling of E coli DH5α, implicating the importance of drug chirality on biological activities at the molecular level.
Highlights
There is great interest in the design of small molecules that selectively target minor grooves of duplex DNA for controlling specific gene expression implicated in a disease
Susceptibility of E coli DH5α to bispyrrole-pyrrolidines To examine the susceptibility of Escherichia coli DH5α (E coli DH5α) towards PySSPy, E coli DH5α treated with variable PySSPy concentrations were examined for their cell growth via OD600 analyses (Additional file 1)
At 9-hr incubation, E coli DH5α treated with 100, 150, 200 and 300 μM PySSPy showed approximately 8 (p < 0.01), 10 (p < 0.001), 12 (p < 0.001) and 20% (p < 0.001) decreases in cell density, respectively
Summary
There is great interest in the design of small molecules that selectively target minor grooves of duplex DNA for controlling specific gene expression implicated in a disease. There is limited research on the chirality effect of minor groove binders on DNA interaction, especially at the protein expression level. We have illustrated that the chiral bispyrrole-pyrrolidine-oligoamides, PySSPy and PyRSPy, showed low binding affinity to DNA, their influence at the proteomic level is significant. Genomics has dramatically altered the way of drug discovery, and as such, small molecules with the ability to sequence-selectively recognize and discriminate between DNA have become increasingly important for the control of specific processes involved in gene expression implicated in diseases [1,2,3,4,5]. It is believed that gene-based expression analysis alone is inadequate for drug discovery
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