Drug Discovery

We take a chemical biology approach to understanding biological mechanisms, we are particularly interested in the selectivity potential of degrader technologies such as PROTACs and AUTACs and how these can be used to expand the druggable chemical universe for Precision Medicine including gene therapy.

Professor David Selwood,
Professor Edith Chan.

Degrader technology: antivirals and cancer.

A recent example is our depsin based PROTACs as shown below. These compounds target the cyclophilin protein in cells to inhibit HIV-1 infection. The combination of the cyclophilin macrocycle and the E3Ligase ligand enable selective degradation of this cyclophilin protein over closely related proteins. The synthesis of these molecules can be seen here: https://www.researchsquare.com/article/rs-2639894/v1 . Other degrader technology is in development https://www.biorxiv.org/content/10.1101/2024.04.15.589474v1

**Selective cyclophilin-A degradation and potent HIV-1 activity.**

Neuropilin: a link between vascular biology, cancer and pain.

The cell surface protein neuropilin-1 is a receptor for several growth factors. These can control signalling in blood vessels, immune regulation for cancer, and as has been recently shown for pain signalling. We were the first to develop inhibitors of neuropilin-1 as reported here https://pubs.acs.org/doi/10.1021/jm901755g and with more potent analogues here: https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00210

**The structure and orientation in the neuropilin-1 binding site as shown by X-ray crystallography.**

Exploiting the big conductance potassium ion channel to protect nerves and support CNS signaling.

The big conductance potassium channel (BK channel) has numerous physiological functions but in the CNS its dysfunction can cause neurodegeneration and intellectual disability. We discovered an isoform specific activator drug (VSN16R) of the channel which has been studied in the clinic as both an anti-spastic agent and for its role in neuroprotection. https://doi.org/10.1111/bph.13889 https://doi.org/10.3390/ph16070972 . BK channel polymorphisms are associated with numerous intellectual disability genes, VSN16R can fix many of these deficits in experimental models such as of Fragile X syndrome. https://doi.org/10.1093/brain%2Fawab246

**Simplified diagram to show myelin distribution around neurons. Oligodendrocytes (green), grow myelin sheaths around axons projecting from neurons (blue). Astrocytes (brown) are in close proximity.**

Select publications

Hurley, MJ, Deacon RMJ, Chan AWE, Baker D, Selwood DL & Cogram P (2022). Reversal of behavioural phenotype by the cannabinoid-like compound VSN16R in fragile X syndrome mice. Brain. Vol. 145(1): 76-82.
Radin DP, Caponegro M, Smith G, Moushiaveshi V, Selwood D & Tsirka S (2022). Studies on the function of myeloid-derived Neuropilin-1 in glioma: a focus on tumour hypoxia. FASEB Journal, Vol. 36(51).
Scott OB, Gu J & Chan AWE (2022). Classification of Protein-Binding Sites Using a Spherical Convolutional Neural Network. Journal of Chemical Information and Modeling. J Chem Inf Model. Vol. 62(22): 5383-5396.
Selwood DL, Mota F, Yelland T, Hutton JA, Parker J, et al. (2021). Peptides Derived from Vascular Endothelial Growth Factor B Show Potent Binding to Neuropilin-1. ChemBioChem.
Gregson A, Thompson K, Tsirka SE & Selwood DL (2019). Emerging small-molecule treatments for multiple sclerosis: focus on B cells. F1000Res, 8.
Briggs LC, Chan AWE, Davis CA ... Selwood DL, Collins MK, Barrett TE (2017). IKKγ-Mimetic Peptides Block the Resistance to Apoptosis Associated with Kaposi's Sarcoma-Associated Herpesvirus Infection. J Virol. Vol. 91(23). pii: e01170-17.
Baker D, Pryce G, Visintin C, Sisay S, Bondarenko AI ... Selwood DL (2017). Big conductance calcium-activated potassium channel openers control spasticity without sedation. Br J Pharmacol. Vol. 174(16): 2662-2681.
Prak K, Kriston-Vizi J, Chan AW, Luft C, Costa JR, Pengo N, Ketteler R. Benzobisthiazoles Represent a Novel Scaffold for Kinase Inhibitors of CLK Family Members. Biochemistry. Vol. 55(3): 608-17.
Warne J, Pryce G, Hill JM, Shi X ... Chan AW, Towers GJ, Coker AR, Duchen MR, Szabadkai G, Baker D, Selwood DL (2016). Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis. J Biol Chem. Vol. 291(9): 4356-73.

Miyauchi JT, Chen D, Choi M, Nissen JC, Shroyer KR, Djordevic S, Zachary IC, Selwood D, Tsirka SE (2016). Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression. Oncotarget. Vol. 7(9): 9801-14.
Browne L, Lidster K, Al-Izki S, Clutterbuck L, Posada C, Chan AW, Riddall D, Garthwaite J, Baker D, Selwood DL (2014). Imidazol-1-ylethylindazole voltage-gated sodium channel ligands are neuroprotective during optic neuritis in a mouse model of multiple sclerosis. J Med Chem. Vol. 57(7): 2942-52. Erratum in: J Med Chem. Vol. 58(8): 3637.
Al-Izki S, Pryce G, Hankey DJ, Lidster K, von Kutzleben SM, Browne L, Clutterbuck L, Posada C, Chan AWE ... Selwood DL, Baker D (2014). Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain. 137(Pt 1): 92-108.
Moyes AJ, Khambata RS, Villar I, Bubb KJ ... Selwood DL, Ahluwalia A, Hobbs AJ (2014). Endothelial C-type natriuretic peptide maintains vascular homeostasis. J Clin Invest. Vol. 124(9): 4039-51.
Aldeghi M, Malhotra S, Selwood DL, Chan AW (2014). Two- and three-dimensional rings in drugs. Chem Biol Drug Des. Vol. 83(4): 450-61.
Rasaiyaah J, Tan CP, Fletcher AJ, Price AJ, Blondeau C, Hilditch L, Jacques DA, Selwood DL et al. (2013). HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature. Vol. 503(7476): 402-405.
Chan AW, Laskowski RA, Selwood DL (2010). Chemical fragments that hydrogen bond to Asp, Glu, Arg, and His side chains in protein binding sites. J Med Chem. Vol. 53(8): 3086-94.
Okuyama M, Laman H, Kingsbury SR, Visintin C, Leo E, Eward KL, Stoeber K, Boshoff C, Williams GH, Selwood DL (2007). Small-molecule mimics of an alpha-helix for efficient transport of proteins into cells. Nat Methods. Vol. 4(2):153-9.