GPCRs and PROTACs: New Approaches for Designing More Effective Drug Candidates

NanoBRET target engagement assay

G protein-coupled receptors (GPCRs) comprise a large group of cell surface receptors, characterized by the unique structural property of crossing the cell membrane seven times. They respond to a diverse group of signaling molecules, such as peptides, neurotransmitters, cytokines, hormones and other small molecules (1). Upon activation, GPCRs interact with GTP-binding (G) proteins and arrestins to regulate a wide variety of signaling pathways. This broad range of functions makes GPCRs attractive targets for drug discovery. The importance of GPCR research was highlighted in 2012, with the Nobel Prize in chemistry being awarded to Robert Lefkowitz and Brian Kobilka “for studies of G-protein–coupled receptors”.

Based on structure and function, GPCRs are categorized into six classes, A–F. The class A GPCRs, or rhodopsin-like receptors, have been studied extensively due to their association with many types of diseases (2). Within the class A GPCRs is a group that share a highly conserved structural motif (3) and respond to chemokines—small “chemotactic cytokines” that stimulate cell migration, especially that of white blood cells (4). A subfamily of class A GPCRs respond to chemokines that have two cysteine residues near the N-terminus, known as CC chemokines. GPCRs activated by CC chemokines are called CC chemokine receptors or CCRs, and these interactions have been implicated in both pro- and anti-cancer pathways (5).

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Psychedelics as Therapeutic Agents: Current Research, Potential Benefits

This past May (2019) the symposium “Psychedelic Therapy in Society: Exploring the Mechanisms of Action and Delivery of Care” was hosted by the International Forum on Consciousness at the BioPharmaceutical Technology Center on the Promega Madison Campus.

Having the good fortune to work across the street at Promega, I was able to attend this two-day conference and learn from leading researchers in psychedelics and about their use in therapy.

My interest in psychedelics is relatively new. I didn’t experiment with these substances during high school or college years. But in recent years, I’ve seen a close relative struggle with profound anxiety related to terminal disease, and another with substance abuse and depression. The lessons learned from each experience is that the battery of medicines used to treat such illness can result in additional problems for which there are currently not good medication options. And in some cases, traditional medications can cause further health problems. Continue reading “Psychedelics as Therapeutic Agents: Current Research, Potential Benefits”