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Cell surface receptors respond to a plethora of extracellular stimuli under several physiological or pathological conditions. Key components of the network, connect and diversify into multiple signal transduction pathways, further amplified by enzymes, cofactors and transcription factors. o2h scientists can quantitatively access drug-target engagement by measuring a variety of intra-cellular signaling events.

Some examples include cAMP, Ca2+, inositol phosphates, phosphoproteins, transcriptional regulation and sub-cellular protein translocation. These events can be sensitively captured using kit-based or bespoke assay designs utilizing different detection platforms like FLIPR, high-content imaging, western blotting, real time qPCR and plate readers.

As a case example, we have highlighted below our experience in GPCR biology wherein there might be an opportunity to screen compounds that are agnosts, partial agonists or antagonists for neuropsychiatric disorders that target serotonin receptors.

A)                                                                                       

Intracellular Signaling_o2h discovery Biology   

Fig A: Chemiluminescent detection of β-Arrestin recruitment in U2OS cells in response to 5-HT (serotonin). Increase in serotonin leads to an increase in luminescence, indicating a dose-dependent β-arrestin recruitment to 5-HT2A receptor. Analysis performed using non-linear regression agonist vs response variable slope (four parameters).

B)                                                                                          C)

Intracellular Signaling_o2h discovery Biology    Intracellular Signaling_o2h discovery Biology

Fig (B, C): Cells stimulated with an Increasing concentration of 5-HT, serotonin measuring intracellular Ca2+ with FLIPR and IP1 levels  detected by HTRF.

D)

Intracellular signaling_o2h discovery Biology

Fig (D): Cells treated with increasing concentration of the antagonist ketanserin exhibiting reduced IP1 generation upon stimulation with EC80 concentration of 5-HT (serotonin).

Serotonin 2A receptor (5-HT2A) plays a key role in mood regulation, cognition, and perception and is activated by the neurotransmitter serotonin. A prototypical psychedelics active Gq/11-mediated activation of PLC, leading to the formation of inositol phosphates, diacylglycerol, followed by Ca2+ release, and β-arrestin2 making their respective roles still unclear.

At o2h discovery, we have developed and screened a series of 5-HT2A-small molecules with varying potencies towards Gq and β-arrestin-biased signaling thererby shedding light on the dynamics associated with the 5-HT2A receptor. These serve as invaluable tools in elucidating the specific intracellular responses providing comprehensive understanding for drug discovery and pharmacological research.

o2h discovery assay setup and cell lines

  • Our o2h scientists can support in identifying compounds with differential signaling activities, downstream of the 5-HT receptor, stimulated via Gαq and beta-arrestin pathways.
  • Stable cell lines overexpressing the receptor of interest e.g. 5HT2A/2B/2C and for different species – human, rat and mouse can be developed in appropriate cellular background for screening. These cells can measure IP1 and Ca2+ as a stable down stream signal utilizing FLIPR to address activation of Gαq pathway.
  • PathHunter-U2OS-HTR2A cell lines from Eurofins/Discoverx can be utilized for the screening of 5HT2A agonists, antagonists and partial agonists in bespoke assays with a transferable license agreement with DiscoverX.
  • These cells overexpress human 5-HT2A receptor and the β-arrestin2. These proteins are engineered to reconstitute β-galactosidase activity upon recruitment of β-arrestin2 to 5-HT2A receptor.
  • We have in the past explored the PathHunter cell line for IP one measurements as well using HTRF-based IP1 kit from CisBio. A significant and reliable fold window is achieved for both IP1 and beta Arrestin with the PathHunter cell line, making it convenient to study biased signalling.

To know more about our biology services offering or to request our brochure, please reach out to us at discovery@o2h.com.

our team

prashant shah

Prashant Shah

CEO - o2h discovery and Co-Founder - o2h group

Prashant's Biography

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Prashant Shah

CEO - o2h discovery and Co-Founder - o2h group

Prashant is a serial entrepreneur in life sciences and tech in which one of those companies was acquired by a public company. He is currently active in seed investing (a portfolio of ~50 companies), product/IP development, services, and building lab/office infrastructure. The early career was with the Strategy group at Accenture. He has a BEng, an MSc, in which he worked on the Human Genome Program at the Sanger Centre, and an MPhil in Management from the Judge Institute. Prashant is also a General Partner in the o2h SEIS/EIS Human Health Funds.


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Sunil

Sunil Shah

CEO - o2h Ventures and Co-Founder - o2h discovery

Sunil's Biography

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Sunil Shah

CEO - o2h Ventures and Co-Founder - o2h discovery

A serial entrepreneur having begun a career in the Life Sciences team at PA Consulting group followed by co-founding two companies in the information technology and life sciences sector. The second of these companies, Oxygen Healthcare Ltd was acquired by Piramal Enterprises Ltd (BSE: PEL). Sunil co-founded o2h ventures which involves discovery services / collaborations, seeding drug discovery, academic in-licensing and biotechnology incubation. Sunil has a degree in Biochemistry and an MBA from Cambridge University


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Andy Morley

Andy Morley

Chief Scientific Officer

Andy's Biography

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Andy Morley

Chief Scientific Officer

Andy is a highly experienced and accomplished Medicinal Chemist with over 25 years of experience in major pharmaceutical companies such as Sanofi-Aventis and AstraZeneca. He has extensive experience across all phases of drug discovery and has played a key role in the development of five candidates that have reached clinical trials. Andy is a prolific author and inventor, with over 55 publications and patents to his name. Since 2013, he has been working full-time with o2h Limited, where he leads the scientific evaluation of investment opportunities and provides scientific support. He has also served as CSO for two early-stage collaborations within the o2h Ventures portfolio, demonstrating his ability to successfully guide drug discovery projects from concept to clinical development.


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David Davies - o2h

David Davies

Head of Medicinal Chemistry

David's Biography

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David Davies

Head of Medicinal Chemistry

David Davies has 25 years of experience in medicinal chemistry within the pharmaceutical industry with a focus on the antibacterial area (clavulanates, penicillinates, pseudomonates and bacterial topoisomerase inhibitors). He previously worked at GSK and currently holds a part-time academic position at University College London (UCL). He served as the Head of Medicinal Chemistry at Antabio for nearly a decade, specialising in antibacterial research, and has extensive experience managing chemistry projects in multiple countries including France, UK, India and China. He is the inventor of 40 patents and has authored 37 publications.


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