A5049845345- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- RNA Interference and Gene Delivery
- Advanced biosensing and bioanalysis techniques
- Antimicrobial Peptides and Activities
- Biochemical and Structural Characterization
- Monoclonal and Polyclonal Antibodies Research
- Autophagy in Disease and Therapy
- Peptidase Inhibition and Analysis
- RNA and protein synthesis mechanisms
- Glycosylation and Glycoproteins Research
- Adenosine and Purinergic Signaling
- Protein Structure and Dynamics
- Biotin and Related Studies
- Lipid Membrane Structure and Behavior
- Microbial Natural Products and Biosynthesis
- Advanced Fluorescence Microscopy Techniques
- DNA and Nucleic Acid Chemistry
- Receptor Mechanisms and Signaling
- Sirtuins and Resveratrol in Medicine
- Toxin Mechanisms and Immunotoxins
- CRISPR and Genetic Engineering
- Influenza Virus Research Studies
- Metal complexes synthesis and properties
- Studies on Chitinases and Chitosanases
Tufts University
2016-2025
Medford Radiology Group
2019
Whitehead Institute for Biomedical Research
2006-2009
Yale University
2004-2006
University of Pennsylvania
2004
hDM2 is recognized in vivo by a short alpha-helix within the p53 trans-activation domain (p53AD). Disruption of p53.hDM2 interaction an important goal for cancer therapy. A functional epitope comprised three residues on one face p53AD helix (F19, W23, and L26) contributes heavily to binding free energy. We hypothesized that would be recapitulated if side chains F19, L26 were presented at successive positions apart stabilized beta3-peptide 14-helix. Here, we report set beta3-peptides possess...
alpha-Synuclein (alpha-syn) is a small lipid-binding protein involved in vesicle trafficking whose function poorly characterized. It of great interest to human biology and medicine because alpha-syn dysfunction associated with several neurodegenerative disorders, including Parkinson's disease (PD). We previously created yeast model pathobiology, which established as process that particularly sensitive expression. also uncovered core group proteins diverse activities related toxicity...
Biotherapeutics are a promising class of molecules in drug discovery, but they often limited to extracellular targets due their poor cell penetration. High-throughput penetration assays required for the optimization biotherapeutics enhanced We developed HaloTag-based assay called chloroalkane (CAPA), which is quantitative, high-throughput, and compartment-specific. demonstrate ability CAPA profile extent cytosolic with respect concentration, presence serum, temperature, time. also used...
Autophagy is an essential pathway by which cellular and foreign material are degraded recycled in eukaryotic cells. Induction of autophagy a promising approach for treating diverse human diseases, including neurodegenerative disorders infectious diseases. Here, we report the use diversity-oriented stapling to produce autophagy-inducing peptides that intrinsically cell-penetrant. These induce at micromolar concentrations vitro, have aggregate-clearing activity model Huntington's disease,...
Effective strategies for mimicking α-helix and β-strand epitopes have been developed, producing valuable inhibitors some classes of protein-protein interactions (PPIs). However, there are no general translating loop into useful PPI inhibitors. In this work, we use the LoopFinder program to identify diverse sets "hot loops," which that mediate PPIs. These include loops well-suited mimicry with macrocyclic compounds, most similar variable on antibodies ankyrin repeat proteins. We present...
The LC3/GABARAP family of proteins is involved in nearly every stage autophagy. Inhibition a promising approach to blocking autophagy, which sensitizes advanced cancers DNA-damaging chemotherapy. Here, we report the structure-based design stapled peptides that inhibit GABARAP with nanomolar affinities. Small changes staple structure produced very different binding modes and functional differences paralog selectivity, ranging from highly GABARAP-specific broad inhibition both subfamilies....
Cellular permeability is an important property in drug discovery and biological probe design. Here we investigate the effect of oxadiazole grafts on cellular using Chloroalkane Penetration Assay.
We report the first structure–activity studies of arylidene–indolinone compound GW5074, which was reported as a ligand autophagy-related protein LC3B. The literature has conflicting information on binding affinity this compound, and there is some debate regarding its use component autophagy-dependent degrader compounds. developed an AlphaScreen assay to measure competitive inhibition known peptide ligands LC3B paralog GABARAP. Eighteen analogs were synthesized tested against both proteins....
Folded polymers are used in Nature for virtually every vital process. Nonnatural folded polymers, or foldamers, have the potential similar versatility, and design refinement of such molecules is considerable current interest. Here we report a complete systematic analysis relationship between side chain structure 14-helicity well-studied class β3-peptides, water. Our experimental results (1) verify importance macrodipole stabilization maintaining 14-helix structure, (2) provide comprehensive...
Small but perfectly formed. A library of miniature protein variants was constructed that presented the minimal recognition epitope human double-minute 2 oncoprotein (hDM2), which derived from activation domain p53 (p53AD). This optimized (see scheme) to yield several proteins with robust folds and nanomolar affinity for hDM2. The inhibitory activities these correlated stability fold. emphasizes benefit presenting p53AD on a scaffold.
In recent decades it has become increasingly clear that induction of autophagy plays an important role in the development treatment resistance and dormancy many cancer types. Unfortunately, chloroquine (CQ) hydroxychloroquine (HCQ), two inhibitors clinical trials, suffer from poor pharmacokinetics high toxicity at therapeutic dosages. This prompted intense interest targeted to re-sensitize disease with minimal impact on normal tissue. We utilized Scanning Unnatural Protease Resistant (SUPR)...
A major obstacle in the development of effective oligonucleotide therapeutics is a lack understanding about their cytosolic and nuclear penetration. To address this problem, we have applied chloroalkane penetration assay (CAPA) to therapeutics. CAPA was used quantitate delivery antisense oligonucleotides (ASOs) siRNAs explore effects wide variety commonly chemical modifications patterning. We evaluated potential artifacts by exploring serum, comparing activity data data, assessing impact tag...
ABSTRACT The development of macrocyclic binders to therapeutic proteins typically relies on large-scale screening methods that are resource-intensive and provide little control over binding mode. Despite considerable progress in physics-based for peptide design deep-learning protein design, there currently no robust approaches de novo protein-binding macrocycles. Here, we introduce RFpeptides, a denoising diffusion-based pipeline designing against targets interest. We test 20 or fewer...
We recently reported a β-peptide foldamer, β53−1, that folds into 14-helix in aqueous solution, binds the oncoprotein hDM2 with submicromolar affinity, and potently inhibits interaction of peptide derived from activation domain p53 (p53AD). Here, we present solution structure β53−1 methanol. Details illustrate fundamental novel elements folding recognition. These include detailed arrangement complex, 14-helix-stabilizing salt bridge on one helical face, unique "wedge cleft" packing along...
Recently we described a β-decapeptide (β53-1) that folds into 14-helix in aqueous solution, binds the oncoprotein hDM2 with submicromolar affinity, and inhibits interaction of peptide derived from activation domain p53 (p53AD). The solution structure β53-1 CD3OH revealed an unexpected C-terminal unwinding staggers side chains comprising recognition epitope to better mimic those p53AD. structure−function relationship implied by this distortion suggested library analogues possessing diversity...
We report the design, synthesis, and characterization of macrocyclic analogues amino-terminal copper nickel binding (ATCUN) motif. These macrocycles have altered pH transitions for metal binding, unlike linear ATCUN motifs, optimal cyclic peptide 1 binds Cu(II) selectively over Ni(II) at physiological pH. UV–vis EPR spectroscopy showed that can coordinate or in a square planar geometry. Metal titration ESI-MS data revealed 1:1 stoichiometry. Macrocyclization allows coordination as but with...