This Small Business Innovation Research Phase I project highlights a strategy for the development of the first integrated high throughput pipeline to synthesize and evaluate novel sugar-drug conjugates. The core innovation of this proposed phase I study is an enzyme catalyzed one-step glycosylation reaction that also presents a convenient colorimetric readout amenable to HT-screening. While this phase I study is focused upon the generation and evaluation of novel sugar-drug conjugates for anticancer activity, the fundamental glycosylation platform described can be applied to the synthesis any type of glycoconjugate. Thus, the methodology described has the potential to greatly advance our understanding and exploitation of the role of complex carbohydrates in biology, engineering and medicine.
The broader/commercial impacts of this research are both immediate and long term. The immediate gain derives from the rapid generation of small molecule glycosides that, as potential drug discovery leads, will advance the field of medicine. The long term impact of the proposed research will stem from the availability of a technology platform for synthesizing complex carbohydrates that can be easily employed by the nonspecialist. With this technology platform, engineers, biologists, and/or physicians will be able to rapidly generate complex carbohydrates to be employed as novel reagents/scaffolds in material science, nanotechnology, engineering, glycobiology and medicine. Thus, successful development of the proposed pipeline described herein is anticipated to transform the role of sugars well beyond the area of therapeutic development.
The first outcome of the NSF Small Business Innovation Research Phase I grant 1046741 was the development and validation of one of the first integrated high throughput pipelines for the synthesis and evaluation of sugar-drug conjugates. The core innovation of this newly devised pipeline is an unparalleled one-step glycosyltransferase (GT)-catalyzed transglycosylation reaction from simple activated glycosyl donors that ultimately drives subsequent target scaffold glycosylation while providing a convenient colorimetric readout amenable to HT-screening. The second outcome of the NSF Small Business Innovation Research Phase I grant 1046741 was the rapid synthesis of large array of small molecule glycosides that, as potential drug discovery leads, may advance the field of medicine. Specifically, as validation of the glycosylation pipeline developed as part of the 1046741 phase I study, the assessment of 724 random bioactive compounds (biased to predominately contain small molecule therapeutics) as possible substrates led to the production of >110 novel glycosides. Notable among these were a series of steroidal-based compounds the glycosides of which are currently under investigation as preclinical leads in cancer and inflammation. While the activity of the newly generated glycosides remains to be fully evaluated, this pilot study clearly demonstrates the speed and efficiency by which the new glycosylation pipeline can generate novel molecules with unique properties. The overall intellectual merit of this work stems from the fact that carbohydrates are ubiquitiuous in nature, are critical to all forms of life and serve in numerous structural and functional capacities. Yet, the specific function of complex carbohydrates in natural processes is often poorly understood due to a lack of practical methods for the preparation of homogeneous complex glycoconjugates for in-depth study. By presenting routine access to structurally/functionally diverse glycoconjugates, the methodology developed as part of this phase I study has the potential to greatly advance our fundamental understanding, and beneficial exploitation, of the role of complex carbohydrates in biology, engineering and medicine. The broader impact of this work are both immediate and long term. The immediate gain derives from the key outcomes described above (namely, a high efficient glycosylation technology platform and a large set of novel bioactive molecules). The long term impact of this work will stem from the availability of a technology platform for synthesizing complex carbohydrates that can be easily employed by the non-specialist. With this robust technology platform in hand, scientists without specialized carbohydrate chemistry training (e.g., engineers, biologists, and physicians) will be able to rapidly generate complex carbohydrates to be employed as novel reagents/scaffolds in material science, nanotechnology, engineering, glycobiology and other aspects of fundamental biology, as well as in the development of novel therapeutics. Thus, the pipeline developed as part of NSF Small Business Innovation Research Phase I grant 1046741 is anticipated to transform the role of sugars well beyond the area of therapeutic development.
