25-30 August 2019
Henry Ford Building
Europe/Berlin timezone

A boost in Drug Discovery with Secondary-labeled Hyperpolarized Ligands

27 Aug 2019, 16:50
25m
Lecture Hall B (Henry Ford Building)

Lecture Hall B

Henry Ford Building

Talk Small molecules Small Molecules

Speaker

Dr Olivier Cala (Université de Lyon, Université Claude Bernard Lyon 1, ENS de Lyon, CNRS, CRMN FRE 2034)

Description

Hyperpolarization by dissolution DNP[1] provides a route to enhancing 13C MR sensitivity by more than four orders of magnitude on a wide range of small molecules. However, many potential applications of dDNP (metabolomics, drug discovery, etc.) would highly benefit from a higher efficiency, throughput, and repeatability of the method.

In this context, we had demonstrated in 2016 that high levels of polarization were reachable in short times (60% in 8 min)[2] and with high repeatability (CV=3.6%)[3].

One important drawback still remains in dDNP which is that it generally relies on low natural abundance 13C spins (1.1%). In 2009, Wilson et al. proposed an approach where amine groups in amino acids were labeled with [1,1-13C] acetic anhydride[4], and subsequently hyperpolarized. Though very promising, this approach had not been taken up by the dDNP community till 2018 where we revisited this secondary labeling approach in the context of NMR drug screening[5]. We have showed how ligands could be secondary labeled, used to probe interactions with target proteins through 13C NMR.

We are now working at combining this concept with dDNP with the aim of decreasing experiment time and sample concentration by orders of magnitudes compared to the classical approach (STD / WaterLOGSY). This has the potential to considerably improve the detection and identification of ligands, and shorten the discovery time of new drug candidates.

References

[1]. Ardenkjaer-Larsen, J. H. et al. Proc. Natl. Acad. Sci. USA 100, 10158–10163 (2003)
[2]. Bornet, A. et al. Phys. Chem. Chem. Phys. 18, 30530–30535 (2016)
[3]. Bornet, A. et al. Anal. Chem. 88, (2016).
[4]. Wilson, D. M. et al. Proc. Natl. Acad. Sci. 106, 5503–5507 (2009)
[5]. Cala, O. et al. Euromar 2018 Nantes France

Primary authors

Dr Olivier Cala (Université de Lyon, Université Claude Bernard Lyon 1, ENS de Lyon, CNRS, CRMN FRE 2034) Quentin Chappuis (Université de Lyon, Université Claude Bernard Lyon 1, ENS de Lyon, CNRS, CRMN FRE 2034) Morgan Ceillier (Université de Lyon, Université Claude Bernard Lyon 1, ENS de Lyon, CNRS, CRMN FRE 2034) Dr Samuel François Cousin (Université de Lyon, Université Claude Bernard Lyon 1, ENS de Lyon, CNRS, CRMN FRE 2034) Houssem-Eddine Boughazi (Université de Lyon, Université Claude Bernard Lyon 1, ENS de Lyon, CNRS, CRMN FRE 2034) Amélie Beck (Université de Lyon, Université Claude Bernard Lyon 1, ENS de Lyon, CNRS, CRMN FRE 2034) Dr Basile Vuichoud (Université de Lyon, Université Claude Bernard Lyon 1, ENS de Lyon, CNRS, CRMN FRE 2034) Dr Aurélien Bornet (Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland) Prof. Sami Jannin (Université de Lyon, Université Claude Bernard Lyon 1, ENS de Lyon, CNRS, CRMN FRE 2034)

Presentation Materials

There are no materials yet.