Biomedical subjects

Steven H Olson

Publications and source records attributed to Steven H Olson.

3 recordsLinked to original sources

PubMed2026

Small molecule inhibition of the mitochondrial lipid transfer protein STARD7 attenuates influenza viral replication.

The increasing appearance of drug-resistant and zoonotic influenza strains highlights an urgent need for host-directed antivirals that offer broad-spectrum activity and a higher barrier to resistance. Here, we describe the characterization of M4, a small-molecule identified from a high-throughput screen that potently inhibits influenza A and B viruses. Mechanistic studies reveal that M4 suppresses influenza virus replication by preventing formation of export-competent viral ribonucleoprotein (vRNP) complexes in the nucleus. Chemoproteomic profiling identified the lipid transfer protein STARD7 as the primary cellular target, and genetic depletion of STARD7 phenocopies the antiviral effects of M4. Additional studies localized the M4 binding site to cysteine 302 within the lipid-binding domain of STARD7, supporting a model in which STARD7-dependent lipid transfer activity promotes efficient vRNP assembly and nuclear export. Combining M4 with baloxavir enhances antiviral efficacy in a murine infection model, providing in vivo support for a host-directed therapeutic strategy. Together, these results identify STARD7 as a metabolic checkpoint licensing vRNP nuclear export and they establish a proof of concept for therapeutic intervention with small molecule inhibitors.

Journal Article↗

PubMed2026

High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction.

The cellular uptake and propagation of tau are central features of tauopathies, including Alzheimer's disease, and are mediated by the endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1). While prior studies have implicated LRP1 in tau binding and internalization, the biochemical features of this interaction and its suitability for therapeutic targeting remain incompletely defined. Here, we establish a quantitative and scalable framework to interrogate the tau-LRP1 interaction and identify small-molecule modulators. We engineered and purified the LRP1 ligand-binding domain 4 (BD4), a key region mediating tau interaction, and developed multiple orthogonal assays, including fluorescence polarization, split luciferase complementation, and time-resolved FRET, to measure LRP1-BD4 interactions with tau and a known peptide ligand. Across assay formats, we observe consistent binding affinities in the nanomolar range and demonstrate competitive displacement by tau, receptor-associated protein (RAP), and a peptide ligand, supporting overlapping binding interfaces. Leveraging these platforms, we performed small molecule high-throughput screening and identified a set of candidate inhibitors of the LRP1-BD4-tau interaction. Selected compounds reduced tau uptake in a cellular assay, phenocopying competitive inhibition by tau and a peptide ligand. Together, these studies define the LRP1-BD4-tau interaction as a biochemically tractable and druggable interface and establish an integrated discovery pipeline linking mechanistic characterization to functional cellular outcomes. This work provides a foundation for the development of therapeutic strategies targeting LRP1-mediated tau uptake.

Journal Article↗

PubMed2026

Structure-guided discovery of non-catechol dopamine D1 receptor ligands with biased agonism and antagonism.

The catechol L-DOPA, a cornerstone of Parkinson's disease (PD) treatment, has two major drawbacks: poor pharmacokinetics and, more significantly, debilitating dyskinesias from chronic dopamine D1 receptor (D1R) activation. Preclinical rodent studies suggest that D1R antagonism or β-arrestin-biased agonism can alleviate these motor complications, highlighting the need for next-generation non-catechol ligands. Through virtual screening, we identified eight novel chemotypes as D1R ligands, including two G protein-biased agonists, two β-arrestin-biased agonists and four antagonists. Structure-activity relationship (SAR) optimization led to the development of A82R, a non-catechol D1R antagonist (Ki 733 nM) with high D1 family over D2 family selectivity. Additionally, we present A69, a novel non-catechol β-arrestin-biased partial agonist for D1R (Ki 86.9 nM, stronger than representative D1R commercial drugs) with a sustained half-life of 1 h in the mouse brain. We show that the observed selectivity patterns are consistent with structural and information-theoretic limits on dopamine's ability to encode receptor subtype identity. Within these bounds, the non-catechol ligand chemotypes represent promising leads for developing therapies that modulate D1R signaling and reduce L-DOPA-induced dyskinesia in PD.

Receptors, Dopamine D1↗