A5081884029- Advanced biosensing and bioanalysis techniques
- RNA Interference and Gene Delivery
- Cannabis and Cannabinoid Research
- Chemical Synthesis and Analysis
- Neurotransmitter Receptor Influence on Behavior
- DNA and Nucleic Acid Chemistry
- Glycosylation and Glycoproteins Research
- Antimicrobial Peptides and Activities
- Forensic Toxicology and Drug Analysis
- Boron Compounds in Chemistry
- Synthetic Organic Chemistry Methods
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Pharmacological Receptor Mechanisms and Effects
- RNA modifications and cancer
- Radiopharmaceutical Chemistry and Applications
- Virus-based gene therapy research
- Chemical Reactions and Isotopes
- Psychedelics and Drug Studies
- Glutathione Transferases and Polymorphisms
- Orthopedic Infections and Treatments
- Nanocluster Synthesis and Applications
- Ubiquitin and proteasome pathways
- Prenatal Substance Exposure Effects
- Cancer Research and Treatments
Massachusetts Institute of Technology
2020-2025
RTI International
2017-2020
The University of Sydney
2018
University of New Orleans
2018
Synthetic cannabinoids are a class of novel psychoactive substances that exhibit high affinity at the cannabinoid type-1 (CB<sub>1</sub>) receptor and produce effects similar to those Δ-9-tetrahydrocannabinol (THC), primary constituent cannabis. Illicit drug manufacturers continually circumventing laws banning sale synthetic by synthesizing structures doing so with little regard for potential impact on pharmacological toxicological effects. wide range include cardiotoxicity, seizure...
Peptide-based cancer vaccines are widely investigated in the clinic but exhibit modest immunogenicity. One approach that has been explored to enhance peptide vaccine potency is covalent conjugation of antigens with cell-penetrating peptides (CPPs), linear cationic and amphiphilic sequences designed promote intracellular delivery associated cargos. Antigen-CPPs have reported enhanced immunogenicity compared free peptides, their mechanisms action vivo poorly understood. We tested eight...
Carboranes represent a class of compounds with increasing therapeutic potential. However, few general approaches to readily embed carboranes into small molecules, peptides, and proteins are available. We report strategy based on palladium-mediated C–X (X = C, S, N) bond formation for the installation carborane-containing moieties onto molecules peptides. demonstrate ability Pd-based reagents appropriate ligands overcome high hydrophobicity carborane group enable chemoselective conjugation...
Synthetic cannabinoids (SCs) are novel psychoactive substances that easily acquired, widely abused as a substitute for cannabis, and associated with cardiotoxicity seizures. Although the structural bases of these compounds scaffolds known affinity efficacy at human cannabinoid type-1 receptor (hCB<sub>1</sub>), upon ingestion or inhalation they can be metabolized to multiple chemical entities unknown pharmacological activity. A large proportion metabolites hydroxylated on pentyl chain, key...
Antisense peptide nucleic acids (PNAs) have yet to translate the clinic because of poor cellular uptake, limited solubility, and rapid elimination. Cell-penetrating peptides (CPPs) covalently attached PNAs may facilitate clinical development by improving uptake into cells. We report an efficient technology that utilizes a fully automated fast-flow instrument manufacture CPP-conjugated (PPNAs) in single shot. The machine is rapid, with each amide bond being formed 10 s. Anti-IVS2-654 PPNA...
Abstract Glioblastoma (GBM) is the most common and deadliest form of brain tumor remains amongst difficult cancers to treat. Brevican (Bcan), a central nervous system (CNS)‐specific extracellular matrix protein, upregulated in high‐grade glioma cells, including GBM. A Bcan isoform lacking glycosylation, dg‐Bcan, found only GBM tissues. Here, dg‐Bcan explored as molecular target for In this study, d ‐peptide library screened identify small 8‐amino acid dg‐ B can‐ T argeting P eptide (BTP)...
Glioblastoma (GBM) is the most common and deadliest malignant primary brain tumor, contributing significant morbidity mortality among patients. As current standard-of-care demonstrates limited success, development of new efficacious GBM therapeutics urgently needed. Major challenges in advancing chemotherapy include poor bioavailability, lack tumor selectivity leading to undesired side effects, permeability across blood-brain barrier (BBB), extensive intratumoral heterogeneity. We have...
Hi1a is a venom peptide isolated from the Australian funnel-web spider Hadronyche infensa, containing an intricate “double knot” tertiary structure and currently under investigation for treatment of ischemic stroke. The recombinant expression chemical synthesis remains significant challenge due to poor yields laborious protocols, delaying progress in translation clinic. Herein, we describe first single-shot (76 amino acids, AA) using automated fast-flow (AFPS), enabling rapid access (4.3 h...
Despite their potential, the preparation of large synthetic macrocyclic libraries for ligand discovery and development has been limited. Here, we produce 100-million-membered containing natural nonnatural amino acids. Near-quantitative intramolecular disulfide formation is facilitated by rapid oxidation with iodine in solution. After use affinity selection, treatment dithiothreitol enables near-quantitative reduction, rendering linear peptide analogs standard tandem mass spectrometry. We...
Allosteric modulators of the cannabinoid CB1 receptor have recently been reported as an alternative approach to modulate for therapeutic benefits. In this study, we report design and synthesis a series diarylureas derived from PSNCBAM-1 (2). Similar 2, these dose-dependently inhibited CP55,940-induced intracellular calcium mobilization [35S]GTP-γ-S binding while enhancing [3H]CP55,940 receptor. Structure-activity relationship studies revealed that pyridinyl ring 2 could be replaced by other...
Macrocyclic peptides are attractive for therapeutic development but have been limited in their application to combinatorial library selection from synthetic libraries. Here, we establish a approach based on split-pool chemistry produce 100-million membered macrocyclic libraries containing natural and non-natural amino acids. Near-quantitative intramolecular disulfide formation is facilitated by rapid (<10 minute) oxidation iodine prepare solution. Treatment with dithiothreitol...
Cell-penetrating peptides (CPPs) can cross the cell membrane to enter cytosol and deliver otherwise nonpenetrant macromolecules such as proteins oligonucleotides. For example, recent clinical trials have shown that a CPP attached phosphorodiamidate morpholino oligomers (PMOs) resulted in higher muscle concentration, increased exon skipping, dystrophin production relative another study of PMO alone patients Duchenne muscular dystrophy. Therefore, effective design CPPs could help enhance...
Abstract Capture and release of peptides is often a critical operation in the pathway to discovering materials with novel functions. However, best methods for efficient capture impede facile release. To overcome this challenge, we report linkers based on secondary amino alcohols after capture. These are serine (seramox) or isoserine (isoseramox) can be incorporated into during solid‐phase peptide synthesis through reductive amination. Both quantitatively cleaved within minutes under NaIO 4...
Peptide-mediated delivery of macromolecules in cells has significant potential therapeutic benefits, but no therapy employing cell-penetrating peptides (CPPs) reached the market after 30 years investigation due to challenges discovery new, more efficient sequences. Here, we demonstrate a method for in-cell penetration selection-mass spectrometry (in-cell PS-MS) discover from synthetic library capable delivering macromolecule cargo cytosol. This was inspired by recent vivo selection...
Allosteric modulators have attracted significant interest as an alternate strategy to modulate CB1 receptor signaling for therapeutic benefits that may avoid the adverse effects associated with orthosteric ligands. Here we extended our previous structure–activity relationship studies on diarylurea-based negative allosteric (NAMs) by introducing five-membered heterocycles replace 5-pyrrolidinylpyridinyl group in PSNCBAM-1 (1), one of first generation modulators. Many these compounds had...
Developing chemical toolkits for mRNA modification has remained an immense challenge driven by inherent difficulties in targeting molecules. Antisense oligonucleotides (ASOs) offer a promising framework specific sequences, yet they do not possess the capacity to alter covalent structure of except through enzyme-mediated hydrolysis. The requirement relying on enzyme modifying incurs several limitations application, design, and delivery ASOs. To address these limitations, we developed...
An expansion of the hexanucleotide (GGGGCC) repeat sequence in chromosome 9 open frame 72 (c9orf72) is most common genetic mutation amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The leads to production toxic dipeptide proteins (DPRs) that induce neurodegeneration. However, fundamental physicochemical properties DPRs remain largely unknown due their limited availability. Here, we synthesized c9orf72 poly-glycine-arginine (poly-GR), poly-proline-arginine (poly-PR),...
Peptide nucleic acids (PNAs) are charge-neutral oligonucleotides with emerging potential for treatment of genetic, acquired, and viral diseases, including COVID-19. Their challenging synthesis, however, limits their use rapid therapeutic intervention widespread application. Here, we report a highly efficient technology that utilizes fully automated fast-flow instrument to manufacture cell-penetrating peptide-conjugated PNAs (PPNAs) in single shot. The machine is rapid: each amide bond formed...
Abstract Barriers in access to clinical care among under-served populations combination with a vast underrepresentation at scientific research level perpetuate inequalities cancer treatment. These disparities are further disseminated due the lack of understanding underlying genomic differences contributing outcome these patients. The contributions germline and somatic variations often shape treatment regimens, not well investigated non-European populations. We have described class potential...
Abstract Peptide-mediated delivery of macromolecules in cells has significant potential therapeutic benefits, but no therapy employing cell-penetrating peptides (CPPs) reached the market after 30 years investigation due to challenges discovery new, more efficient sequences. We developed a method for in-cell penetration selection-mass spectrometry (in-cell PS-MS) discover from synthetic library capable delivering macromolecule cargo cytosol. This was inspired by recent vivo selection...
Abstract Capture and release of peptides is often a critical operation in the pathway to discovering materials with novel functions. However, best methods for efficient capture impede facile release. To overcome this challenge, we report linkers based on secondary amino alcohols after capture. These are serine (seramox) or isoserine (isoseramox) can be incorporated into during solid‐phase peptide synthesis through reductive amination. Both quantitatively cleaved within minutes under NaIO 4...