Hyun Suk Lim

Novel pyrrolopyrimidine-based α-helix mimetics: cell-permeable inhibitors of protein−protein interactions.

There is considerable interest in developing non-peptidic, small-molecule α-helix mimetics to disrupt α-helix-mediated protein−protein interactions. Herein, we report the design of a novel pyrrolopyrimidine-based scaffold for such α-helix mimetics with increased conformational rigidity. We also developed a facile solid-phase synthetic route that is amenable to divergent synthesis of a large library. Using a fluorescence polarization-based assay, we identified cell-permeable, dual MDMX/MDM2 inhibitors, demonstrating that the designed molecules can act as α-helix mimetics.

Potent and selective photo-inactivation of proteins with peptoid-ruthenium conjugates

Advances in high-throughput screening now enable the rapid discovery of bioactive small molecules, but these primary hits almost always exhibit modest potency. We report a strategy for the transformation of these hits into much more potent inhibitors without compound optimization. Appending a derivative of Ru(II)(tris-bipyridyl)2+, an efficient photosensitizer of singlet oxygen production, to synthetic protein-binding compounds results in highly potent and specific target protein inactivation upon irradiation with visible light.

A short and efficient stereoselective synthesis of all four diastereomers of sphingosine

Abstract Practical syntheses of all four stereomers of sphingosine from serine have been achieved through highly diastereoselective reduction of the N-trityl protected α′-amino enone derivative 5 with NaBH4 and reduction of the free α′-amino enone derivative 7 with Zn(BH4)2.

Reductively degradable polyester-based block copolymers prepared by facile polycondensation and ATRP: synthesis, degradation, and aqueous micellization

Well-defined reductively degradable amphiphilic block copolymers having disulfide linkages positioned repeatedly on hydrophobic chains, thus exhibiting fast degradation, were prepared by a combination of polycondensation and ATRP. The new method consists of three synthetic steps including, (1) polycondensation of commercially available diols and diacids through carbodiimide coupling or high temperature processes to synthesize degradable polyesters with disulfides labeled on the main chain at regular intervals (ssPES–OH), (2) bromination of ssPES–OH to ssPES–Br, and (3) ATRP for chain extension of ssPES–Br with water-soluble polymethacrylate, yielding ssPES-b-polymethacrylate block copolymers (ssABPs). The reductive cleavage of disulfide linkages in reducing conditions resulted in the degradation of ssPES homopolymers; their degradation rate was significantly enhanced with the increasing amounts of disulfide linkages in ssPES–OH and reducing agents. For ATRP, gel permeation chromatography and 1H-NMR results confirmed the synthesis of well-defined ssABPs and revealed that polymerizations were well controlled. Because of their amphiphilic nature, ssABPs self-assembled in water toward the formation of core/shell micelles consisting of a hydrophobic ssPES core surrounded with polymethacrylate coronas. The effects of the coronas chain length on thermal properties and micellization in water of well-defined ssABPs were examined. Moreover, reductive (or thiol-responsive) degradation of ssABP-based micelles enabled fast release of encapsulated model drugs. Cell culture experiments confirmed nontoxicity and biocompatibility of well-defined ssABPs as effect candidates for targeted delivery applications.

Amot130 Adapts Atrophin-1 Interacting Protein 4 to Inhibit Yes-associated Protein Signaling and Cell Growth

Background: Amot130 regulates cell differentiation and growth signaling. Results: Amot130 binds and activates overexpressed AIP4 to ubiquitinate Amot130 and YAP resulting in Amot130 stabilization and YAP degradation. Conclusion: Amot130 and AIP4 cooperatively inhibit YAP and cell growth. Significance: A mechanism is described whereby Amot130 directs AIP4 to potentially suppress tumor cell growth. The adaptor protein Amot130 scaffolds components of the Hippo pathway to promote the inhibition of cell growth. This study describes how Amot130 through binding and activating the ubiquitin ligase AIP4/Itch achieves these effects. AIP4 is found to bind and ubiquitinate Amot130 at residue Lys-481. This both stabilizes Amot130 and promotes its residence at the plasma membrane. Furthermore, Amot130 is shown to scaffold a complex containing overexpressed AIP4 and the transcriptional co-activator Yes-associated protein (YAP). Consequently, Amot130 promotes the ubiquitination of YAP by AIP4 and prevents AIP4 from binding to large tumor suppressor 1. Amot130 is found to reduce YAP stability. Importantly, Amot130 inhibition of YAP dependent transcription is reversed by AIP4 silencing, whereas Amot130 and AIP4 expression interdependently suppress cell growth. Thus, Amot130 repurposes AIP4 from its previously described role in degrading large tumor suppressor 1 to the inhibition of YAP and cell growth.

Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein–protein interactions

α-Helices are the most common protein secondary structure and play a key role in mediating many protein-protein interactions (PPIs) by serving as recognition motifs. Given that aberrant α-helix-mediated PPIs are linked to various disease states, targeting such interactions with small-molecules represents an attractive strategy to develop therapeutic candidates for the related diseases. Over the last decade, significant efforts have been directed toward developing α-helix mimetic small-molecules that can modulate α-helix-mediated PPIs. In this review, we will highlight recent advances in the development of non-peptidic, small-molecule α-helix mimetics with a focus on library synthesis and screening methods to efficiently discover small-molecule α-helix mimetics.

Design and Facile Solid-Phase Synthesis of Conformationally Constrained Bicyclic Peptoids

Triazine-bridged bicyclic peptoids as conformationally constrained peptidomimetics are described. Bicyclic peptoids composed of 6-12 peptoid residues (m, n = 3-6) were synthesized in excellent yields using a highly efficient solid-phase synthetic route.

Syntheses of sphingosine-1-phosphate stereoisomers and analogues and their interaction with EDG receptors

Sphingosine-1-phosphate (S1P) is considered to be an important regulator of diverse biological processes acting as a natural ligand to EDG receptors. As a preliminary study to develop potent and selective agonist and antagonist for EDG receptors, we report synthesis of S1P stereoisomers and analogues and their binding affinities to EDG-1, -3, and -5.

Rapid identification of the pharmacophore in a peptoid inhibitor of the proteasome regulatory particle

Here we report a simple and effective method to identify the minimal pharmacophore in the first peptoid inhibitor of the 19S proteasome regulatory particle, which has led to the development of a derivative that exhibits improved cellular activity, presumably due to a reduction in mass of about two-fold and the elimination of positively charged lysine-like residues.

Rapid identification of improved protein ligands using peptoid microarrays

A rapid array-based protocol is presented by which a modest affinity protein-binding small molecule can be appended to a library of peptoids via click chemistry. The array can then be screened for improved ligands that exhibit a higher affinity for the protein target.