Novel drug delivery systems, detection methods, and drug screens for therapeutic development
The NeurdyPhagy Lab is currently studying novel drugs that regulate S-acylation in HD and ALS and developing new drug screens against novel targets recently identified in our lab.
Previously, detection of fatty acylated proteins required the use of radioactive fatty acids that were unsafe, laborious, and required long detections times, days to months. As a PhD student, in collaboration with Nobel Laureate Dr. Carolyn Bertozzi (Martin et al 2008), Dr. Martin developed a new protocol using biorthogonal fatty acids that could be covalently linked to biotin via click chemistry. The NeurdyPhagy recently published an optimized version (Liao et al). Click chemistry is now the primary method for studying N-myristoylation and a standard method for the detection of S-acylation. As a postdoctoral fellow in the Hayden Lab at UBC, Dr. Martin helped conceive of and optimize nanodisks to deliver ASOs non-invasively through intravenous injection (Caron et al) and intranasal uptake (Aly et al). These nanodisks were based on Dr. Martin’s previous work on ApoA-I (Martin et al 2006). Subsequently, Dr. Martin helped design a high-throughput screening method to identify inhibitors of Dual Leucine Zipper Kinase (DLK) S-palmitoylation (Martin et al 2019).
Selected Pubs
Caron, N.S., Aly, A.E., Black, H.F., Martin, D.D.O., Schmidt, M.E., Ko, Y., Anderson, C., Casal, L.L., Anderson, L.M., Rahavi, R.S.M., Reid, G.S.D., Oda, M.N., Stanimirovic, D., Abulrob, A., McBride, J.L., Leavitt, B.R., Hayden, M.R. (2024) Apolipoprotein A-I nanodiscs as vehicles for delivering HTT-targeted antisense oligonucleotides to the central nervous system for Huntington disease. Journal of Controlled Release PMID: 38215984
Aly, AE, Caron, NS, Black, HF, Schmidt, ME, Anderson, C, Ko, S, Baddeley, HJE, Anderson, L, Casal, LL, Rahavi, RSM, Martin, DDO, Hayden, MR (2023) Delivery of mutant huntingtin-lowering antisense oligonucleotides to the brain by intranasally administered apolipoprotein A-I nanodiscs. Journal of Controlled Release Vol 360, pg 913-927.
Liao, LMQ, Gray, RAV, Martin, DDO1 (2021) Optimized delivery of alkyne fatty acids for the detection of fatty acylation using Click Chemistry. J. Vis. Exp. e62107(170). PMID: 33900285 Open Access
·Martin, DDO, Kanuparthi P, Holland, SM, Sanders, SS, Jeoung, H, Einarson, M, Jacobson, M, Thomas, GM (2019) Identification of novel inhibitors of DLK palmitoylation by High Content Screening. Scientific Reports 9(3632). PMID: 30842471 Available on BioRxiv
Martin, DDO, Vilas, GL, Prescher, JA, Rajaiah, G, Falck, JR, Bertozzi, CR, Berthiaume, LG (2008) Rapid detection, discovery and identification of post-translationally myristoylated proteins during apoptosis using a bioorthogonal azidomyristate analogue. FASEB J. 22(3):797-806 PMID: 17932026
Martin, DDO, Budamagunta, MS, Ryan, RO, Voss, JC, Oda, MN (2006) Apolipoprotein A-I assumes a “Looped Belt” conformation on reconstituted high density lipoprotein. J. Biol Chem. 281(29): 20418-26. PMID: 16698792