A5020418271- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Antimicrobial Peptides and Activities
- Biochemical and Structural Characterization
- Microbial Natural Products and Biosynthesis
- Computational Drug Discovery Methods
- Arctic and Russian Policy Studies
- Protein Degradation and Inhibitors
- RNA and protein synthesis mechanisms
- Advanced biosensing and bioanalysis techniques
- Marine Sponges and Natural Products
- Lipid Membrane Structure and Behavior
- Cancer-related Molecular Pathways
- Food Industry and Aquatic Biology
- Chemical Reactions and Mechanisms
- Big Data Technologies and Applications
- Plant biochemistry and biosynthesis
- Peptidase Inhibition and Analysis
- Coenzyme Q10 studies and effects
- Cytokine Signaling Pathways and Interactions
- Cruise Tourism Development and Management
- Analytical Chemistry and Chromatography
- Supramolecular Self-Assembly in Materials
- Electrochemical Analysis and Applications
- Carbohydrate Chemistry and Synthesis
University of California, Santa Cruz
2013-2020
Whittier College
2010-2013
Significance Natural products research seems to be at a critical juncture in terms of its relevance modern biological science. We have evaluated this landscape chemical diversity ask key questions, including the following. How has rate discovery new natural progressed over past 70 y? Has product structural novelty changed as function time? novel declined recent years? Does exploring taxonomic space afford an advantage compound discovery? Is it possible estimate how close we are describing...
Drug design efforts are turning to a new generation of therapeutic targets, such as protein-protein interactions (PPIs), that had previously been considered "undruggable" by typical small molecules. There is an emerging view accessing these targets will require molecules larger and more complex than molecule drugs. Here, we present methodology for the discovery geometrically diverse, membrane permeable cyclic peptide scaffolds based on synthesis permeability screening combinatorial library,...
As drug discovery moves increasingly toward previously "undruggable" targets such as protein-protein interactions, lead compounds are becoming larger and more lipophilic. Although increasing lipophilicity can improve membrane permeability, it also incur serious liabilities, including poor water solubility, increased toxicity, faster metabolic clearance. Here we introduce a new efficiency metric, especially relevant to "beyond rule of 5" molecules, that captures, in simple, unitless value,...
Macrocyclic peptides are considered large enough to inhibit "undruggable" targets, but the design of passively cell-permeable molecules in this space remains a challenge due poorly understood role molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed library cyclic, per-N-methlyated spanning wide range calculated lipohilicities (0 < AlogP 8) and weights (∼800 Da MW ∼1200 Da). Analysis by parallel artificial permeability assay revealed steep...
Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino other derived from polyketide synthases. We hypothesized that the position orientation these extended backbone impact ADME properties hybrid molecules, especially their ability to cross cell membranes avoid metabolic degradation. Here we report synthesis hexapeptide diastereomers containing...
It is well established that intramolecular hydrogen bonding and N-methylation play important roles in the passive permeability of cyclic peptides, but other structural features have been explored less intensively. Recent studies on oral bioavailability heptapeptide sanguinamide A raised question whether steric occlusion polar groups via β-branching an effective, yet untapped, tool peptide optimization. We report structures 17 analogues designed to test relative contributions β-branching,...
Synthetic and natural cyclic peptides provide a testing ground for studying membrane permeability in nontraditional drug scaffolds. Cyclic peptomers, which incorporate peptide N-alkylglycine (peptoid) residues, combine the stereochemical geometric complexity of with functional group diversity accessible to peptoids. We synthesized peptomer libraries by split-pool techniques, separately permuting side chain backbone geometry, analyzed their permeabilities using parallel artificial assay....
Few tools exist in natural products discovery to integrate biological screening and untargeted mass spectrometry data at the library scale. Previously, we reported Compound Activity Mapping as a strategy for predicting compound bioactivity profiles directly from primary results on extract libraries. We now present NP Analyst, an open online platform that accepts bioassay of almost any type, is compatible with major instrument manufacturers via mzML format. In addition, Analyst will accept...
Abstract Large macrocyclic peptides can achieve surprisingly high membrane permeability, although the properties that govern permeability in this chemical space are only beginning to come into focus. We generated two libraries of cyclic decapeptides with stable cross‐β conformations, and found peptoid substitutions within β‐turns macrocycle preserved rigidity parent scaffold, whereas opposing β‐strands led “chameleonic” species were rigid nonpolar media but highly flexible water. Both...
Cyclic peptide (CP) natural products provide useful model systems for mapping "beyond-Rule-of-5" (bRo5) space. We identified the phepropeptins as product CPs with potential cell permeability. Synthesis of and epimeric analogues revealed much more rapid cellular permeability stereochemical pattern. Despite being permeable, compounds exhibited similar aqueous solubility corresponding epimers, a phenomenon explained by solvent-dependent conformational flexibility among compounds. When analyzing...
Constrained, membrane-permeable peptides offer the possibility of engaging challenging intracellular targets. Structure-permeability relationships have been extensively studied in cyclic whose backbones are cyclized from head to tail, like membrane permeable and orally bioavailable natural product cyclosporine A. In contrast, physicochemical properties lariat peptides, which one termini onto a side chain, received little attention. Many peptide products exhibit interesting biological...
Synthetic macrocyclic peptides are an emerging molecular class for both targeting intracellular protein–protein interactions (PPIs) and providing oral modality drug targets typically addressed by biologics. Display technologies, such as mRNA phage display, often yield that too large polar to achieve passive permeability or bioavailability without substantial off-platform medicinal chemistry. Herein, we use DNA-encoded cyclic peptide libraries discover a neutral nonapeptide, UNP-6457,...
Despite the prevalence of head-to-side chain threonine linkages in natural products, their incorporation has been underexplored synthetic cyclic peptides. Herein we investigate a peptide scaffold able to undergo an N–O acyl rearrangement. Upon acylation amine with diverse carboxylic acids, resulting depsipeptides displayed favorable cellular permeability and conformation similar parent peptide. The rearrangement was found be dependent as evidenced by molecular dynamics experiments.
Abstract Large macrocyclic peptides can achieve surprisingly high membrane permeability, although the properties that govern permeability in this chemical space are only beginning to come into focus. We generated two libraries of cyclic decapeptides with stable cross‐β conformations, and found peptoid substitutions within β‐turns macrocycle preserved rigidity parent scaffold, whereas opposing β‐strands led “chameleonic” species were rigid nonpolar media but highly flexible water. Both...
Two α-diimine ligands were prepared in 60–70% yield via p-toluenesulfonic acid-catalyzed condensation reactions from benzil with 4-bromoaniline and p-anisidine. Palladium(II) complexes both 70–80% yield. X-ray structures obtained for the ligand p-anisidine its palladium(II) complex. A notable feature observed former was unconjugated C–N double bonds, (E)-configuration. The latter structure possessed two molecules of metal complex unit cell, which have diimine cores a degree conjugation...