Many traditional drugs inhibit enzyme function; in contrast, some naturally “sticky” small molecules can stabilize protein-protein interactions. In this issue of Cell Chemical Biology, Kaplan et al. (2020) explore regulation of the 14-3-3 interactome by a small-molecule molecular glue leading to neurite outgrowth through a polypharmacological mechanism.

Qu et al. (2020) demonstrate a peptide-induced targeted degradation of the alpha-synuclein protein, a hallmark of Parkinson’s disease. Using a modular three-component design, the target-protein-specific, cell-permeable peptide disposed of alpha-synuclein via the ubiquitin-proteasome pathway rather than the standard autophagy-lysosome pathway.

In this issue of Cell Chemical Biology, Harvey et al. (2020) identify 4E14, a sulfhydryl-containing N-acetyltryptophan analog that selectively disrupts binding to the previously undruggable anti-apoptotic BCL2 paralog BFL1, and elucidate a BFL1 conformational change that facilitates 4E14 interaction. These results provide insight that will accelerate development of BFL1 inhibitors.

In this issue of Cell Chemical Biology, White et al. (2020) describe CRISPR/Cas9-mediated tagging of GPCRs and β-arrestin to provide a method to study receptor signaling in cells under conditions of endogenous genetic control. The strategy, when coupled with luminescence reporter and complementation technologies, provides new avenues to study GPCRs.

In this issue of Cell Chemical Biology, Chen et al. (2020) present an antibody-based platform to generate Wnt agonists, offering multiple design principles for systematic investigation of Wnt activation. This study lays the groundwork to develop potent Wnt agonists for applications in regenerative medicine.

In this issue of Cell Chemical Biology, Erdogan et al. (2020) describe a new CRISPR/Cas9-based strategy for performing directed evolution of mammalian proteins in situ. Using this technique to select functional mRuby3 variants within lysosomes, they identify mCRISPRed, a fluorescent protein that displays robust stability and activity at low pH.

Proteolysis-targeting chimeras (PROTACs) is a paradigm shift for small-molecule drug discovery. However, limited E3 ubiquitin ligase ligands with cellular activity are available. In vitro binding assays involve the expression and purification of a large amount of proteins and they often yield ligands that are inactive in cell-based assays due to poor cell permeability, stability, and other reasons

Ferroptosis is an iron-dependent cell-death modality driven by oxidative phospholipid damage. In contrast to apoptosis, which enables organisms to eliminate targeted cells purposefully at specific times, ferroptosis appears to be a vulnerability of cells that otherwise use high levels of polyunsaturated lipids to their advantage. Cells in this high polyunsaturated lipid state generally have safeguards

Carbamoyl phosphate synthetase 1 (CPS1) drives ammonia conversion to carbamoyl phosphate, and its overexpression supports pyrimidine synthesis and tumor growth, highlighting the potential of CPS1 inhibition as a therapeutic target. In this issue of Cell Chemical Biology, Yao et al. (2020) introduce H3B-120 as a promising novel inhibitor of CPS1.

In this issue of Cell Chemical Biology, Caplan et al. (2020) describe a series of studies in the human fungal pathogen Candida albicans to identify a new target for antimicrobial drug development. Beginning with an unbiased compound screen, they identify new mechanisms to address rising resistance to currently used anti-infective agents.

In a recent issue of Cell Chemical Biology, Gray et al. (2020) report an aptamer-based method to reversibly label and isolate EGF receptor-expressing cells from heterogeneous mixtures by cell sorting approaches. Subsequent treatment using complementary oligonucleotides restores full functionality of EGF receptors, highlighting the superiority of this method to antibody-based sorting.