We are a dynamic, interdisciplinary, medium-size lab working at the interface of chemistry and biology. We work on the development of probes to visualize and control biological processes in living sys...

This Special Issue in _ACS Chemical Biology_ will highlight the latest advancements and perspectives in the chemical biology of lipids and lipidation. Submit your manuscript by May 31, 2026.

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

Phosphoinositide signaling is a major cellular mechanism controlling cancer cell viability, proliferation, and survival. Yet, inhibition of lipid kinases that produce oncogenic phosphoinositides has afforded only a limited number of efficacious drugs attributed in large part to on-target toxicity resulting from the pleiotropic effects of these signaling lipids. Targeting the specific phosphoinositide effector pathways via competitive inhibitors of phosphoinositide-recognizing pleckstrin homology (PH) domains represents a relatively unexplored means to achieve greater specificity. Herein, we present the discovery from in silico screening, structure–activity relationship (SAR) optimization, and cellular characterization of novel phosphoinositide-competitive inhibitors of the pleckstrin homology domain-containing A (PLEKHA) family. These compounds induce cytotoxic effects in BRAF and NRAS mutant melanoma cells, consistent with on-target inhibition, and the most potent compound is activated by endogenous esterase activity, suggesting that prodrug esters represent a viable strategy for targeting the phosphoinositide-binding pockets of the PLEKHA family of PH domains.

An approach combining bioorthogonal chemistry with genetically encoded fluorogen-activating proteins enables subcellular imaging of phospholipids and glycans, as well as the visualization of lipid tra...

RNA targeting represents a compelling strategy for addressing challenging therapeutic targets that are otherwise intractable through traditional protein targeting. Revolutionary approaches in RNA-focused small molecule libraries have successfully identified RNA-binding ligands but generally remain limited in diversity and impeded by a dearth of structural insight into RNA and RNA complexes. Cyclic peptides are potential structural mimics of evolutionary RNA-protein interacting motifs and can be massively diversified and selected via genetically encoded libraries, offering a complementary approach. This study introduces genetically encoded thioether cyclic peptide libraries constructed through mRNA display using a dibromoxylene linker and its fluorosulfonyl derivative that can covalently engage RNA nucleophiles. Using an optimized mRNA display workflow for RNA binders, we discovered high affinity, covalent and noncovalent binders for SNCA 5′ UTR IRE, the upstream iron-responsive element that post-transcriptionally regulates the expression of α-synuclein, an intrinsically disordered protein implicated in Parkinsonism and related neurodegenerative diseases. Notably, a stringent selection strategy employing “base-paired” target analog counterselection enhanced specificity by deenriching nonspecific electrostatic interactions mediated by polycationic residues. Further engineering hit peptides with an imidazole tag yielded selective RNA degraders in which covalent degraders showed noticeably improved potency from noncovalent counterparts. This work provides a prototype framework for evolution-driven, high-throughput, RNA-targeted drug discovery using cyclic peptides.

A chemigenetic reporter assay is developed that enables monitoring of BiP/GRP78 expression, an important chaperone and key regulator of the unfolded protein response. The system is based on the coexp....

Abstract. G protein-coupled receptors regulate diverse physiological functions in mammalian cells. Methods enabling temporal control of individual G protei

Paraptosis is a distinct form of programmed cell death characterized by cytoplasmic vacuolization, mitochondrial swelling, and endoplasmic reticulum (ER) dilation, offering an alternative to apoptosis...

Job #AJO30338, WDR-00054776 Assistant Professor - Chemistry and Chemical Biology, Cornell University (Ithaca, NY), Chemistry and Chemical Biology, Cornell University, Ithaca, New York, US

Organelles feature characteristic lipid compositions that lead to differences in membrane properties. In cells, membrane ordering and fluidity are commonly measured using the solvatochromic dye Laurdan, whose fluorescence is sensitive to lipid packing. As a general lipophilic dye, Laurdan stains all hydrophobic environments in cells; therefore, it is challenging to characterize membrane properties in specific organelles or assess their responses to pharmacological treatments in intact cells. Here, we describe the synthesis and application of Laurdan-derived probes that read out the membrane packing of individual cellular organelles. The set of organelle-targeted Laurdans (OTL) localizes to the ER, mitochondria, lysosomes, and Golgi compartments with high specificity while retaining the spectral resolution needed to detect biological changes in membrane ordering. We show that ratiometric imaging with OTLs can resolve membrane heterogeneity within organelles as well as changes in lipid packing resulting from inhibition of trafficking or bioenergetic processes. We apply these probes to characterize organelle-specific responses to saturated lipid stress. While the ER and lysosomal membrane fluidity is sensitive to exogenous saturated fatty acids, that of mitochondrial membranes is protected. We then use differences in ER membrane fluidity to sort populations of cells based on their fatty acid diet, highlighting the ability of organelle-localized solvatochromic probes to distinguish between cells based on their metabolic state. These results expand the repertoire of targeted membrane probes and demonstrate their application in interrogating lipid dysregulation.

The lipid composition of cellular membranes is highly dynamic and undergoes continuous remodeling, affecting the biophysical properties critical to biological function. Here, we introduce an optical a...

Highlighted Article: A front-localized positive feedback loop among Ras, Rac1 and Rab5, underlies front-side identity and integrates spatial cues into EGFR-Ras-ERK signaling during collective cell mig...