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Designer macrocyclic organo-peptide hybrids inhibit the interaction between p53 and HDM2/X by accommodating a functional ?-helix.

ABSTRACT: We report the design of side-chain-to-tail linked organo-peptide hybrids incorporating an ?-helical protein-binding motif. Using this strategy, macrocyclic inhibitors of the p53:HDM2 interaction displaying dual specificity against the HDMX homolog as well as increased proteolytic stability could be obtained.

SUBMITTER: Smith JM

PROVIDER: S-EPMC4480681 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Designer macrocyclic organo-peptide hybrids inhibit the interaction between p53 and HDM2/X by accommodating a functional α-helix.

Smith Jessica M JM Frost John R JR Fasan Rudi R

Chemical communications (Cambridge, England) 20140407 39

We report the design of side-chain-to-tail linked organo-peptide hybrids incorporating an α-helical protein-binding motif. Using this strategy, macrocyclic inhibitors of the p53:HDM2 interaction displaying dual specificity against the HDMX homolog as well as increased proteolytic stability could be obtained. ...[more]

PMID: 24710524

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Project description:BACKGROUND:SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology. However, rationally engineering specific inhibitors that interfere with transcription factor DNA interfaces continues to be a monumental challenge in the field of transcription factor chemical biology. Polyoxometalates (POMs) are inorganic compounds that were previously shown to target the high-mobility group (HMG) of SOX proteins at nanomolar concentrations. In continuation of this work, we carried out an assessment of the selectivity of a panel of newly synthesized organo-polyoxometalate hybrids in targeting different transcription factor families to enable the usage of polyoxometalates as specific SOX transcription factor drugs. RESULTS:The residual DNA-binding activities of 15 different transcription factors were measured after treatment with a panel of diverse polyoxometalates. Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class. Further, organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity. The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency. CONCLUSION:Polyoxometalates are highly potent, nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family. However, binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families. Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR. In summary, our report reaffirms that transcription factors are challenging molecular architectures and that future polyoxometalate chemistry must consider further modification strategies, to address the substantial challenges involved in achieving target selectivity.

Dataset Information

Designer macrocyclic organo-peptide hybrids inhibit the interaction between p53 and HDM2/X by accommodating a functional ?-helix.

Publications

Designer macrocyclic organo-peptide hybrids inhibit the interaction between p53 and HDM2/X by accommodating a functional α-helix.

Similar Datasets

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