Alexander Sebastian Hauser

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The explosion of biomedical data such as in genomics, structural biology and pharmacology can provide new opportunities to improve our understanding of human physiology and disease. G protein-coupled receptors (GPCRs) mediate a vast variety of critical biological processes and provide an ideal case study on the focused integration of these amounts of data with innovative computational tools to gain novel insights into receptor biology. My PhD focused on how to harness the biodata revolution i) to identify new trends in GPCR drug discovery, ii) to investigate how subtle genetic variations can imbalance GPCR signalling, iii) to discover novel human signalling systems and iv) to understand the determinants of selectivity between receptors and their signalling partners.

I am now trying to provide a basis for genetics-based personalised drug prescriptions for some of the most commonly used CNS drugs acting on G protein-coupled receptors (GPCRs), and to create a public research platform to characterise GPCR genetic variants (funded by Lundbeck)

What are the current trends in GPCR drug discovery? (I)

We reported a recent analysis of all GPCR drugs and agents in clinical trials, which revealed current trends across drug targets, molecule types and therapeutic indications. The field is readily exploring previously untargeted receptors such as peptide and protein GPCRs and is investigating new types of agents such as monoclonal antibodies, recombinant proteins and allosteric modulators. The advent of GPCR structures are starting to impact drug discovery and new opportunities are emerging for GPCR targeted agents in oncology and metabolic diseases.

What is the prevalence of natural genetic variation in GPCRs? (II)

By integrating genomics data and GPCR structure data we found that several GPCRs targeted by drugs show extensive genetic variation in the human population. We showed that this variation occurs in parts of the GPCR protein that matter for the drug response. For example, we observed polymorphisms in the GPCR targeted by morphine and painkillers, which may explain why antidotes to an opioid overdose may not always work. This is a good example of how an integrative, data-science based approach can provide new insights and potentially have an impact on society and healthcare

Can we identify new hormones for uncharacterised (orphan) receptors? (III)

We investigated the human peptide signalling system and universal characteristics of peptide ligands and their cognate receptors. With these insights, we select putative peptide binding receptors among class A orphan GPCRs and design a library of potentially new endogenous peptide ligands. We identified multiple new receptor-ligand pairs in a multifaceted screening approach, with 26 new ligands paired with 5 receptors among additional indicative pairings for 5 receptors.

How is receptor-G protein selectivity determined? (IV)

We laid the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins. Universally conserved patterns of amino acids in the G proteins are recognised by individual receptors differently through distinct residues - like non-identical cuts in keys (receptors) opening the same lock (G proteins).

 

I am a member of the Personalised Medicine cluster, the Gloriam Group, and the Institute of Biological Psychiatry

As the president of the CBioVikings, RSG International Society for Computational Biology (ISCB), I have been trying to provide a networking platform and learning opportunity for Bioinformaticians and computational Biologists in the Copenhagen Area.

Twitter: @alexshauser

Udvalgte publikationer

1. Udgivet

   Pharmacogenomics of GPCR Drug Targets

   Hauser, Alexander Sebastian, Chavali, S., Masuho, I., Jahn, L., Martemyanov, K., Gloriam, David E. & Babu, M., jan. 2018, I: Cell. 172, s. 41–54

   Publikation: Bidrag til tidsskrift › Tidsskriftartikel › fagfællebedømt

2. Udgivet

   Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors

   Foster, S. R., Hauser, Alexander Sebastian, Vedel, L., Strachan, R. T., Huang, X., Gavin, A. C., Shah, S. D., Nayak, A. P., Haugaard-Kedström, L. M., Penn, R. B., Roth, B. L., Bräuner, Hans & Gloriam, David E., 31 okt. 2019, I: Cell. 179, 4, s. 895-908

   Publikation: Bidrag til tidsskrift › Tidsskriftartikel › fagfællebedømt

3. Udgivet

   Trends in GPCR drug discovery: new agents, targets and indications

   Hauser, Alexander Sebastian, Gloriam, David E., Attwood, M. M., Rask-Andersen, M. & Schiöth, H. B., 27 okt. 2017, I: Nature Reviews. Drug Discovery. 16, s. 829-842 14 s., 178.

   Publikation: Bidrag til tidsskrift › Tidsskriftartikel › fagfællebedømt

4. Udgivet

   Selectivity determinants of GPCR-G-protein binding

   Flock, T., Hauser, Alexander Sebastian, Lund, N., Gloriam, David E., Balaji, S. & Babu, M. M., 18 maj 2017, I: Nature. 545, 7654, s. 317-322 6 s.

   Publikation: Bidrag til tidsskrift › Tidsskriftartikel › fagfællebedømt

Udvalgte priser

1. H.C. Ørsted forskertalentpris

   Hauser, Alexander Sebastian (Modtager), 14 aug. 2019

   Pris: Priser, stipendier, udnævnelser