Janarthanan Jayawickramarajah

Affiliations:

• Tulane Cancer Center
• Tulane Vector Borne Infectious Diseases Research Center
• Tulane Lung Biology Program
• Tulane Bio-innovation Program

Research interests include Nanobiotechnology, Molecular Recognition and Self-Assembly.

Exquisitely controlled self-assembly in water is a key modality used by Nature to build highly functional biological systems. Research in the Jayawickramarajah group involves a highly interdisciplinary effort to develop bio-inspired functional molecules capable of undergoing specific molecular recognition events. A main thrust of our research is to study water compatible, self-assembling, synthetically functionalized oligomers that address contemporary problems.  We are currently focused on the following research areas.

1. The Chemistry and Self-Assembly of Macrocyclic Host-DNA Conjugates. The focus of our scientific research is at the interface of supramolecular chemistry with biology and materials. In particular, we have recently pioneered the nascent field of Host-DNA conjugates. This field involves the imbrication of synthetic macrocyclic hosts with DNA sequences. Such chimeric systems can exploit the programmability and controllability of DNA with the orthogonal molecular recognition and interesting functionality of synthetic hosts leading to highly functional and dynamic assemblies (e.g., input-responsive nanomachines and biomarker triggered protein inhibitors) that thrive in aqueous environments. Robust molecular recognition in water is a critical strength since most synthetic molecular recognition systems fail in water (as a result of insolubility issues and/or competing interactions with water).

Representative Publications

Kankanamalage, D. V. D. W.; Tran, J. H. T.; Beltrami, N.; Meng, K.; Zhou, X.; Pathak, P.; Isaacs, L,; Burin, A. L.; Ali, M. F.; Jayawickramarajah, J. DNA strand displacement driven by host-guest interactions. J. Am. Chem. Soc. 2022. DOI:10.1021/jacs.2c05726.

Pandey, S.; Kankanamalage, D.; Zhou, X.; Hu, C.; Isaacs, L,; Jayawickramarajah, J.; Mao, H. Chaperone assisted host-guest interactions revealed by single-molecule force spectroscopy. J. Am. Chem. Soc. 2019. 141, 18395-18389. DOI:10.1021/jacs.9b09019.

Zhou, X.; Pathak. P.; Jayawickramarajah, J. Design, synthesis, and applications of DNA-macrocyclic host conjugates. Chem Comm. 2018, 54, 11668-11680. DOI: 10.1039/c8cc06716c.

2. Bright, Non-Aggregating, Porphyrin/Fluorophore Arrays. The antenna complexes used in natural photosynthesis are predominantly composed of densely packed light-absorbing porphyrin-like pigments (chlorophyll- or bacteriochlorophyll-pigments) that are specifically positioned, and protected from self-stacking, by self-assembling peptide scaffolds. While nature has mastered the construction of exquisite photonic self-assemblies that are densely packed with chromophores, a long-standing hurdle that needs to be overcome to fully develop synthetic nanostructures composed of arranged chromophores (especially in water) is the minimization of dye-dye aggregation. Such dye contact can significantly attenuate the photophysical properties of the chromophores (e.g., quenching of excited states) thereby precluding the use of the excited state for subsequent processes. As importantly, increasing dye density can substantially compromise the nanostructured assembly due to competing hydrophobic interactions and even result in the formation of ill-defined aggregates and precipitates. Our group has constructed synthetic (and photonic) nanostructures, including nanowires and nanospheres wherein macrocycle (e.g., cyclodextrin) based host-guest interactions are used to prevent chromophore aggregation.

Representative Publications

Pathak, P.; Zarandi, M. A.; Zhou, X.; Jayawickramarajah, J. Synthesis and applications of porphyrin-biomacromolecule conjugates. Front. Chem. 2021, 9, 764137. DOI: 10.3389/fchem.2021.764137

Pathak, P.; Yao, W.; Hook, K. D.; Vik, R.; Winnerdy, F. R.; Brown, J. Q.; Gibb, B. C.; Pursell, Z F.; Phan, A. T.; Jayawickramarajah, J. Bright G-quadruplex nanostructures functionalized with porphyrin lanterns. J. Am. Chem. Soc. 2019, 141, 12582-12591. DOI: 10.1021/jacs.9b03250.

Zhang, H.; Zhang, B.; Zhu, M.; Grayson, S.; Schmehl, R.; Jayawickramarajah, J. Water-soluble porphyrin nanospheres: Enhanced photo-physical properties achieved via cyclodextrin driven double self-inclusion, Chem Comm. 2014, 50, 4853-4855. DOI:10.1039/C4CC01372G.

Fathalla, M.; Li, S.-C.; Neuberger, A. Schmehl, R.; Diebold, U.; Jayawickramarajah, J. Straightforward self-assembly of porphyrin nanowires in water: Harnessing adamantane/β-cyclodextrin interactions J. Am. Chem. Soc. 2010, 132, 9966-9967. DOI: 10.1021/ja1030722.

3. DNA-Small Molecule Chimeras (DCs) as Input Activated Protein Binders. We are developing novel DNA-small molecule chimeras (DCs) that serve as input-triggered protein binders/inhibitors. The generation of such novel inhibitor activation strategies is critical since traditional approaches to activate prodrugs are largely limited to covalent activation (e.g., enzyme or light mediated prodrug triggering). Since our strategy uses molecular recognition-based activation, it is possible to significantly expand the types of biomarkers (e.g., non-enzyme proteins, oligonucleotides, and small metabolites) that can be harnessed.

Representative Publications

Zhou, X.; Su, X.; Pathak, P.; Vik, R.; Vinciguerra, B.; Isaacs, L.; Jayawickramarajah, J. Host-Guest tethered DNA transducer: ATP fueled release of a protein inhibitor from cucurbit[7]uril. J. Am. Chem. Soc. 2017, 139, 13916-13921. DOI: 10.1021/jacs.7b07977.

Chu, X.; Battle, C.; Zhang, N.; Aryal, G. H.; Jayawickramarajah, J. Bile acid conjugated DNA chimera that conditionally inhibits carbonic anhydrase-II in the presence of microRNA-21. Bioconjugate Chemistry 2015, 26, 8,1601-1612. DOI:10.1021/acs.bioconjchem.5b00231.

Harris, D. C.; Saks, B. R.; Jayawickramarajah, J. Protein-binding molecular switches via host-guest stabilized DNA hairpins. J. Am. Chem. Soc. 2011, 133, 7676-7679. DOI: 10.1021/ja2017366.

Harris, D. C.; Chu, X; Jayawickramarajah, J. DNA-small molecule chimera with responsive protein-binding ability.

J. Am. Chem. Soc. 2008, 130, 14950-14951. DOI: 10.1021/ja806552c.