Synergistic and generalizable approaches to disease diagnosis and treatment are necessary to sustain the growing number of patients and diseases worldwide. Furthermore, the increasing prevalence of drug-resistant bacteria and cancer mutations necessitate new treatment strategies. Here, I present a novel approach for the sequential detection and treatment of diseases that have distinctive metabolic features. The key component of this proposal is the invention of bioorthogonal complexation? selective, high-affinity, host-guest chemistries that rely on abiotic functionality. Previously, bioorthogonal chemistry has been employed to detect the metabolic incorporation of unnatural functional groups. These covalent chemistries have lead to an explosion of new information about biological processes; however, their performance has come up short in living animals due to slow reaction kinetics, background reactivity and/or large unnatural functional groups. Non-covalent chemistry will overcome these limitations, as association rates are diffusion controlled and activated functional groups are unnecessary. Furthermore, the reversibility of host-guest chemistry will allow for sequential imaging and therapeutics, a new avenue for theranostics. As opposed to the kinetic challenges of bioorthogonal chemistry that many researchers have focused on for over fifteen years, bioorthogonal complexation represents an unexplored thermodynamic challenge. Historically, host-guest chemistry has focused on the creation of new macrocycles, which are then assayed against different guests. With bioorthogonal complexation, the design strategy is reversed to focus on small, unique guests and the rational design of hosts for these guests using bioorthogonal intermolecular interactions. This proposal contains two avenues which we will simultaneously explore: 1) the validation of bioorthogonal complexation and the tandem diagnostic-therapeutic strategy using known host-guest chemistry and 2) the rational design, synthesis, and evaluation of bioorthogonal host-guest pairs which will be implemented for diagnostics and therapeutics. In the first avenue, we will employ cucurbit[n]uril hosts that will be combined with guest-modified cells or antibodies to determine the affinity and avidity requirements for bioorthogonal complexation in cellulo and in vivo. In the second avenue, we will use the tools of computation and organic synthesis to create novel host-guest chemistries that can be applied for targeting metabolically incorporated guests. Taken together, research derived from this proposal will significantly impact the fields of computational chemistry, supramolecular chemistry, chemical biology, and medicine.

Public Health Relevance

New methods to detect and treat disease are essential for the advancement of medicine. We design ?lock and key? molecules that have exquisite selectivity for each other. The ?key? molecules can be selectively associated with disease sites through the introduction of a modified metabolite and the ?lock? can be employed to deliver an imaging agent or therapeutic, enabling both detection and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2GM132680-01
Application #
9562393
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Okita, Richard T
Project Start
2018-09-30
Project End
2023-05-31
Budget Start
2018-09-30
Budget End
2023-05-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095