Terphenyl‐Based Helical Mimetics That Disrupt the p53/HDM2 Interaction

Yin, Hang; Lee, Gui-in; Park, Hyung Soon; Payne, Gregory A.; Rodriguez, Johanna M.; Sebti, Saı̈d M.; Hamilton, Andrew D.

doi:10.1002/anie.200462316

Cited by 238 publications

(179 citation statements)

References 24 publications

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“…In a separate study, the interaction of active terphenyl compounds with the p53-binding pocket on MDM2 has also been detected by displacement of fluorescent p53 peptide and by induction of chemical shift changes at residues that form the p53-binding pocket in 15 N-HSQC nuclear magnetic resonance (25). These results are consistent with a mechanism of p53 activation by direct competition for MDM2 binding.…”

Section: Induction Of P53 Accumulation and Activation In Vivosupporting

confidence: 58%

p53 α-Helix mimetics antagonize p53/MDM2 interaction and activate p53

Chen

Yin

Farooqi

et al. 2005

Molecular Cancer Therapeutics

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Overexpression or hyperactivation of MDM2 contributes to functional inactivation of wild-type p53 in nearly 50% of tumors. Inhibition of p53 by MDM2 depends on binding between an NH 2 -terminal (residues 16 -28) p53 A-helical peptide and a hydrophobic pocket on MDM2, presenting an attractive target for development of inhibitors against tumors expressing wild-type p53. Here we report that novel p53 A-helical peptide mimics based on a terphenyl scaffold can inhibit MDM2-p53 binding in vitro and activate p53 in vivo. Several active compounds have been identified that inhibit MDM2-p53 binding in an ELISA assay with IC 50 of 10 to 20 Mmol/L and induce p53 accumulation and activation in cell culture at 15 to 40 Mmol/L. These results suggest that p53 A-helical mimetics based on the terphenyl scaffold may be developed into potent p53 activators. [Mol Cancer Ther 2005;4(6): 1019 -25]

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Section: Induction Of P53 Accumulation and Activation In Vivosupporting

confidence: 58%

p53 α-Helix mimetics antagonize p53/MDM2 interaction and activate p53

Chen

Yin

Farooqi

et al. 2005

Molecular Cancer Therapeutics

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“…The results reported here represent a substantial advance relative to earlier efforts to develop unnatural oligomers that mimic ␣-helices involved in protein-protein recognition events (13,14,28,(41)(42)(43)(44)(45)(46). Previous work has been limited to relatively short ␣-helical targets, typically only two to four helical turns.…”

Section: Discussionmentioning

confidence: 89%

Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers

Horne

Johnson

Ketas

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

257

269

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Unnatural oligomers that can mimic protein surfaces offer a potentially useful strategy for blocking biomedically important proteinprotein interactions. Here we evaluate an approach based on combining ␣-and ␤-amino acid residues in the context of a polypeptide sequence from the HIV protein gp41, which represents an excellent testbed because of the wealth of available structural and biological information. We show that ␣/␤-peptides can mimic structural and functional properties of a critical gp41 subunit. Physical studies in solution, crystallographic data, and results from cell-fusion and virusinfectivity assays collectively indicate that the gp41-mimetic ␣/␤-peptides effectively block HIV-cell fusion via a mechanism comparable to that of gp41-derived ␣-peptides. An optimized ␣/␤-peptide is far less susceptible to proteolytic degradation than is an analogous ␣-peptide. Our findings show how a two-stage design approach, in which sequence-based ␣3␤ replacements are followed by site-specific backbone rigidification, can lead to physical and biological mimicry of a natural biorecognition process.alpha/beta-peptides ͉ HIV ͉ protein folding ͉ protein-protein interactions I dentification of strategies for interference with specific biopolymer recognition processes constitutes a fundamental challenge. Protein-protein associations are often resistant to inhibition by small molecules because the contact surfaces on the natural partners are large (1). Current clinical approaches to inhibiting proteinprotein interactions that underlie viral infection or aberrant signaling at the cell surface are based on the use of medium-length peptides or proteins (2). It would be valuable to identify alternative sources of antagonists for this type of protein recognition event.Here we show that peptide-like oligomers with unnatural backbones can function as potent antiviral agents by blocking a key protein-protein interaction. The design strategy we employ may prove general for ␣-helix mimicry.The HIV membrane protein gp41 mediates viral envelope-host cell membrane fusion, an essential step in the viral infection cycle. During HIV cell entry, the N-terminal fusion segment of trimeric gp41 inserts into the host cell membrane (3). A profound structural rearrangement of gp41 ensues, driven by formation of an antiparallel six-helix bundle (4-6), which leads to juxtaposition of the viral and host cell membranes. The prehairpin fusion intermediate is composed of three copies of gp41 in an extended conformation. The so-called ''class I'' fusion mechanism used by HIV is common to a variety of enveloped viruses, including those responsible for influenza, Ebola, and SARS (7,8). A number of ␣-peptides based on sequences from the gp41 N-terminal heptad repeat (NHR) domain or C-heptad repeat (CHR) domain (e.g., Fig. 1B, 1 and 2) have been investigated as anti-HIV agents (9, 10). These compounds are thought to act by binding to a gp41 prehairpin intermediate, thereby preventing six-helix bundle formation and subsequent virus-cell fusion. The drug enfu...

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“…In lieu of the natural amide backbone of a-helical peptides, synthetic scaffolds have been developed that effectively present critical amino acid residues to the antiapoptotic groove. For example, constructing compounds using terphenyl, 125,126 terpyridine, 127 or terephthalamide 128 scaffolds that project essential BH3 motifs yielded groove binders with micromolar and nanomolar K d s (Figure 6b). Gellman and co-workers 129 developed BAK BH3 'foldamers' that are peptidic compounds built from oligomers with defined folding propensities.…”

Section: Rebuilding the Bh3 Helixmentioning

confidence: 99%

BCL-2 in the crosshairs: tipping the balance of life and death

Walensky¹

2006

Cell Death Differ

225

175

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The discovery of B-cell lymphoma-2 (BCL-2) over 20 years ago revealed a new paradigm in cancer biology: the development and persistence of cancer can be driven by molecular roadblocks along the natural pathway to cell death. The subsequent identification of an expansive family of BCL-2 proteins provoked an intensive investigation of the interplay among these critical regulators of cell death. What emerged was a compelling tale of guardians and executioners, each participating in a molecular choreography that dictates cell fate. Ten years into the BCL-2 era, structural details defined how certain BCL-2 family proteins interact, and molecular targeting of the BCL-2 family has since become a pharmacological quest. Although many facets of BCL-2 family death signaling remain a mechanistic mystery, small molecules and peptides that effectively target BCL-2 are eliminating the roadblock to cell death, raising hopes for a medical breakthrough in cancer and other diseases of deregulated apoptosis.

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Terphenyl‐Based Helical Mimetics That Disrupt the p53/HDM2 Interaction

Cited by 238 publications

References 24 publications

p53 α-Helix mimetics antagonize p53/MDM2 interaction and activate p53

p53 α-Helix mimetics antagonize p53/MDM2 interaction and activate p53

Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers

BCL-2 in the crosshairs: tipping the balance of life and death

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