This proposal describes the design and development of versatile amphiphilic dendrimer-based supramolecular assemblies, in aqueous milieu, that disassemble in response to specific proteins as stimuli. There have been great advances in stimuli-sensitive supramolecular assemblies; however, these have primarily focused on systems that respond to changes in factors such as pH, temperature, or redox conditions, which are secondary imbalances in biology. The most direct and primary indicator of imbalance in biology involves change in protein activity. Therefore, generating supramolecular assemblies that respond to proteins is exciting. Our primary objective is to obtain a better understanding of the structural factors that control the assembly/disassembly events in response to the concentration of a specific protein or activity of an enzyme. The structural requirements for achieving control over these assembly/disassembly events are quite stringent. This proposal describes the first, concerted approach to achieve controlled disassembly of dendrimer-based amphiphilic assemblies in response to a specific protein stimulus, in order to understand those structural requirements. We take three complementary approaches to disassemble the dendrimer assemblies through interaction with proteins: (i) where the protein non-covalently binds to specific ligand functionalities in the dendrimer; (ii) where the proteins induce a covalent modification of the functionalities of the dendrimers; and (iii) where two enzymes with opposing functional group transformation capabilities render the supramolecular assemblies perform work only in the presence of a biological energy source. The proposed research will result in a novel, protein- responsive supramolecular platform with implications in several biomedical applications.

Public Health Relevance

This project describes new strategies for stimuli-responsive disassembly of supramolecular assemblies formed from facially amphiphilic dendrimers and oligomers, specifically protein-based stimuli. Since disassembly can cause concurrent guest release, this will ultimately provide novel protein-responsive therapeutic strategies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Fabian, Miles
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University of Massachusetts Amherst
Schools of Arts and Sciences
United States
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