Biology subjects

Hauser, A. S.

Publications and source records attributed to Hauser, A. S..

5 recordsLinked to original sources

bioRxiv2026

De novo macrocyclic peptide discovery produces potent class A GPCR ligands with diverse pharmacology

G protein-coupled receptors (GPCRs) represent one of the largest protein families of therapeutic importance, as over one third of all currently approved drugs target GPCRs. A growing proportion of GPCR drugs are peptides. However, class A GPCRs (over 80% of clinically studied targets) are underexploited as peptide targets, presumably since their only structured domain is the core, seven-helix, integral membrane fold presenting a limited solvent-exposed surface area. Screening libraries of de novo macrocyclic peptides have allowed for the targeting of otherwise intractable proteins, but their potential to generate selective ligands for class A GPCRs has not been demonstrated. Here, we used random nonstandard peptides integrated discovery (RaPID) to identify de novo macrocyclic peptide ligands targeting the chemokine receptor CXCR4. CXCR4 regulates cell migration, immune surveillance, and inflammation, making it an important therapeutic target for multiple diseases. We discovered novel, potent CXCR4-selective antagonists binding within the orthosteric pocket with nanomolar affinity. The most active peptides effectively inhibited receptor signaling, suppressed chemokine-driven cell migration, and blocked CXCR4-driven HIV entry. Our results show that even the structurally minimal class A GPCRs are viable targets for de novo cyclic peptide discovery, highlighting the potential for uncovering ligands towards other members of the GPCR superfamily.

pharmacology and toxicology↗

bioRxiv2026

PrimeKG-Plus: a literature-derived expansion of a multimodal precision medicine knowledge graph

BackgroundDisease-centered knowledge graphs (KGs) support drug repurposing and precision medicine research, yet many remain static after release while primary databases and literature continue to expand. PrimeKG (Precision Medicine Knowledge Graph) is a widely used multimodal KG providing a holistic view of diseases. However, its public release reflects a June 2021 data cutoff, omitting several years of subsequent data growth. This lag is especially consequential for rare diseases, where mechanistic and therapeutic evidence often remains scattered across publications rather than structured resources. FindingWe present PrimeKG-Plus, a refreshed, rare-disease-enriched release of PrimeKG, rebuilt from all twenty original data resources updated to their December 2025 releases and three additional resources: OpenTargets, RepurposeDrugs, and nSIDES. Beyond synchronizing biomedical databases, PrimeKG-Plus captures approximately five years of previously unavailable rare-disease knowledge from the biomedical literature, curated from 637 PubMed abstracts and PubMed Central full-text articles using a language-model-assisted workflow focused on four rare neurological disorders: Canavan disease, Niemann-Pick disease type C, Tay-Sachs disease, and Batten disease. Extracted relations were refined through entity normalization, UMLS synonym mapping, embedding-based similarity ranking, and human expert review. Network topology analysis showed improved indirect drug-disease connectivity across three to six hops and added 447,288 drug-protein-disease paths linking previously unreachable drug-disease pairs. Temporal validation using drug approval records identified 55 molecular entities approved after the original PrimeKG June 2021 cutoff, 46 of which were absent from the original graph. ConclusionPrimeKG-Plus restores the temporal relevance of PrimeKG, providing an updated resource for drug repurposing, rare-disease research, and downstream machine-learning applications.

bioinformatics↗

bioRxiv2024

The sodium leak channel NALCN is regulated by neuronal SNARE complex proteins

The sodium leak channel NALCN is vital for the regulation of electrical activity in neurons and other excitable cells, and mutations in the channel or its auxiliary proteins lead to severe neurodevelopmental disorders. Here we show that the neuronal SNARE complex proteins syntaxin and SNAP25, which enable synaptic transmission in the nervous system, inhibit the activity of the NALCN channel complex in both heterologous systems and primary neurons. The existence of this interaction suggests that the neurotransmitter release machinery can regulate electrical signalling directly, and therefore modulate the threshold for its own activity. We further find that reduction of NALCN currents is sufficient to promote cell survival in syntaxin-depleted cells. This suggests that disinhibited NALCN may cause the puzzling phenomenon of rapid neuronal cell death in the absence of syntaxin. This interaction may offer opportunities for future drug development against genetic diseases linked to both NALCN- and SNARE protein-containing complexes.

neuroscience↗

bioRxiv2021

GPCR-G protein selectivity - a unified meta-analysis

Two-thirds of human hormones and one-third of clinical drugs act on membrane receptors that couple to G proteins to achieve appropriate functional responses. While G protein transducers from literature are annotated in the Guide to Pharmacology database, two recent large-scale datasets now expand the receptor-G protein couplome. However, these three datasets differ in scope and reported G protein couplings giving different coverage and conclusions on GPCR-G protein signaling. Here, we report a common coupling map uncovering novel couplings supported by both large-scale studies, the selectivity/promiscuity of GPCRs and G proteins, and how the co-coupling and co-expression of G proteins compare to the families from phylogenetic relationships. The coupling map and insights on GPCR-G protein selectivity will catalyze advances in receptor research and cellular signaling towards the exploitation of G protein signaling bias in design of safer drugs.

pharmacology and toxicology↗

bioRxiv2020

Selectivity Landscape of 100 Therapeutically Relevant GPCR Profiled by an Effector Translocation-Based BRET Platform

The recognition that individual GPCRs can activate multiple signaling pathways has raised the possibility of developing drugs selectively targeting therapeutically relevant ones. This requires tools to determine which G proteins and {beta}arrestins are activated by a given receptor. Here, we present a set of BRET sensors monitoring the activation of the 12 G protein subtypes based on the translocation of their effectors to the plasma membrane (EMTA). Unlike most of the existing detection systems, EMTA does not require modification of receptors or G proteins (except for Gs). EMTA was found to be suitable for the detection of constitutive activity, inverse agonism, biased signaling and polypharmacology. Profiling of 100 therapeutically relevant human GPCRs resulted in 1,500 pathway-specific concentration-response curves and revealed a great diversity of coupling profiles ranging from exquisite selectivity to broad promiscuity. Overall, this work describes unique resources for studying the complexities underlying GPCR signaling and pharmacology.

pharmacology and toxicology↗