A5003557201- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Monoclonal and Polyclonal Antibodies Research
- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- DNA and Nucleic Acid Chemistry
- Carbohydrate Chemistry and Synthesis
- RNA modifications and cancer
- Genetics, Bioinformatics, and Biomedical Research
- Biochemical and Structural Characterization
- Various Chemistry Research Topics
- Supramolecular Self-Assembly in Materials
- Synthetic Organic Chemistry Methods
- Enzyme Structure and Function
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Glycosylation and Glycoproteins Research
- Advanced biosensing and bioanalysis techniques
- Synthesis and Catalytic Reactions
- Peptidase Inhibition and Analysis
- Genomics and Chromatin Dynamics
- Cancer-related gene regulation
- SARS-CoV-2 and COVID-19 Research
New York University
2016-2025
University of California, Irvine
1998-2013
American Cancer Society
2013
University of California, Berkeley
2013
California Institute of Technology
2002-2012
University of Arizona
2009
East China Normal University
2009
Cornell University
2008
Memorial Sloan Kettering Cancer Center
2002
Structure-based design of synthetic inhibitors protein-protein interactions (PPIs) requires adept molecular and synthesis strategies as well knowledge targetable complexes. To address the significant gap between elegant helix mimetics their sporadic use in biology, we analyzed full set helical protein interfaces Protein Data Bank to obtain a snapshot how helices that are critical for complex formation interact with partner proteins. The results this study expected guide systematic PPIs. We...
Abstract The emergence of SARS-CoV-2 has caused over a million human deaths and massive global disruption. viral infection may also represent threat to our closest living relatives, nonhuman primates. contact surface the host cell receptor, ACE2, displays amino acid residues that are critical for virus recognition, variations at these modulate susceptibility. Infection studies have shown some primate species develop COVID-19-like symptoms; however, susceptibility most primates is unknown....
Alpha-helices constitute the largest class of protein secondary structures and play a major role in mediating protein-protein interactions. Development stable mimics short alpha-helices would be invaluable for inhibition This Account describes our efforts developing general approach constraining peptides alpha-helical conformations by main-chain hydrogen bond surrogate (HBS) strategy. The HBS feature carbon-carbon derived from ring-closing metathesis reaction place an N-terminal...
Herein we describe a strategy for the preparation of artificial α-helices involving replacement one main-chain hydrogen bonds with covalent linkage. To mimic CO···H−N bond as closely possible, envisioned type CX−Y−N, where X and Y are two carbon atoms connected through an olefin metathesis reaction. Our results demonstrate that between i + 4 residues at N-terminus short peptide carbon−carbon in highly stable constrained α-helix physiological conditions indicated by CD NMR spectroscopies. The...
Nonpeptidic foldamers capable of displaying protein-like functionality were prepared by swapping amide bonds with 1,2,3-triazole rings. The overall conformation these triazole oligomers is largely dictated dipole−dipole interactions between adjacent Solution NMR studies suggest that a zigzag conformation, which closely mimics the β-strand structure, predominates in two different tetramers.
Synthetic inhibitors of protein−protein interactions are being discovered despite the inherent challenge in targeting large contact surfaces with small molecules. An analysis available examples identifies common features complexes that make them tractable for We deduced relative disposition and energetic contributions "hot spot" residues provide a predictive scale potential to be inhibited by On basis this model, we analyzed full set helical protein interfaces Protein Data Bank identify...
Designed ligands that inhibit hypoxia-inducible gene expression could offer new tools for genomic research and, potentially, drug discovery efforts the treatment of neovascularization in cancers. We report a stabilized alpha-helix designed to target binding interface between C-terminal transactivation domain (C-TAD) factor 1alpha (HIF-1alpha) and cysteine-histidine rich region (CH1) transcriptional coactivator CBP/p300. The synthetic helix disrupts structure function this complex, resulting...
Herein we identify and analyze helical protein interfaces as potential targets for synthetic modulators of protein–protein interactions.
Protein–protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce relative positioning and disposition important residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led development novel synthetic inhibitors complexes, direct mimicry natural amino acid does not lead potent inhibitors....
The development of inhibitors for protein-protein interactions frequently involves the mimicry secondary structure motifs. While helical have been heavily targeted, a similar level success inhibition β-strand and β-sheet rich interfaces has elusive. We describe an assessment full range whose high-resolution structures are available in Protein Data Bank. This analysis identifies complexes where β-stand or contributes significantly to binding. results highlight molecular recognition complexity...
Significance Protein–protein interactions are attractive targets for drug design due to their fundamental role in biological function. However, small molecules that selectively target the intended have been difficult access using traditional discovery approaches. We show compounds reproduce key functionality at interface between transcription factor hypoxia-inducible 1α (HIF1α) and coactivator p300 (or CREB binding protein, CBP) can inhibit expression of a multitude genes under hypoxic...
Artificial α helices prepared by the replacement of a hydrogen bond between residues i and i+4 with carbon–carbon can stabilize biologically relevant peptides in helical conformations (1, internal constraint shaded gray). Helices based on hydrogen-bond surrogates that mimic Bak BH3 (2, yellow) bind their expected protein receptor, Bcl-xL green), high affinity resist proteolytic degradation. Supporting information for this article is available WWW under...
We previously reported the design and synthesis of a new class artificial α-helices in which an N-terminal main-chain hydrogen bond is replaced by carbon−carbon derived from ring-closing metathesis reaction [Chapman, R. N.; Dimartino, G.; Arora, P. S. J. Am. Chem. Soc. 2004, 126, 12252−12253]. Our initial study utilized alanine-rich sequence; present manuscript we evaluate potential this method for very short (10 residues) representing two different biologically relevant α-helical domains....
We recently developed a new class of oligomers that contain α-amino acid residues linked by 1,2,3-triazole groups [Angelo, N. G.; Arora, P. S. J. Am. Chem. Soc. 2005, 127, 17134−17135]. Synthesis these involves an iterative sequence consisting diazotransfer and Huisgen 1,3-dipolar cycloaddition steps. In this contribution, we describe efficient one-pot, two-step for the preparation triazoles from corresponding amino acid-derived amines alkynes in solution. The one-pot affords desired...
Split kit: Synthetic helices target chosen protein–protein interactions with high specificity, as assessed by an in vitro split-protein reassembly assay. By using the p53/MDM2 complex a model system, both efficacy of designed ligands and suitability assay were determined. Detailed facts importance to specialist readers are published "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They made available submitted authors. Please note: The publisher is...
Significance Protein–protein interactions are attractive targets for interfering with processes leading to disease states. Proteins often use folded domains or secondary structures contact partner proteins. Synthetic molecules that mimic these could disrupt protein–protein contacts, thereby inhibiting formation of multiprotein complexes. This article describes protein domain mimetics (PDMs) modulate between two proteins control expression a multitude genes under hypoxic environments, such as...
A new class of nonpeptidic α-helix mimetics derived from α-amino acids and featuring chiral backbones is described. NMR circular dichroism spectroscopies, in combination with molecular modeling studies, provide compelling evidence that oligooxopiperazine dimers adopt stable conformations reproduce the arrangement i, i+4, i+7 residues on an α-helix.
The incidence of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) has rapidly increased over the past 30 years, prompting suggestion that an epidemic maybe on horizon. Therefore, there is a clinical need to develop alternate therapeutic strategies manage growing number HPV-positive HNSCC patients. High-risk HPV E6 inactivates p53 through two distinct mechanisms; association with E6AP degrade p300 block p300-mediated acetylation activation. In this study, we...
Chemoselective reactions for amide bond formation have transformed the ability to access synthetic proteins and other bioconjugates through ligation of fragments. In these ligations, is accelerated by transient enforcement an intramolecular reaction between carboxyl amine termini two Building on this principle, we introduce aldehyde capture that parlays high chemoselective reactivity aldehydes amines enforce amino acid residues peptides are difficult ligate existing technologies.