At the subcellular level, humans like other organisms build and choreograph the countless structures essential to maintaining a healthy life by the process of self-assembly. Cells are in fact, enormously complex supramolecular entities that employ supramolecular nanoconstruction. Yet, improper self- assembly can also lead to diseases such as Alzheimer's, sickle-cell anaemia, etc. Therefore, mastering molecular self-assembly in aqueous media can lead to great advances in developing novel diagnostics and therapeutics. Supramolecular chemistry offers an attractive strategy for constructing self-made nanostructures by programming the appropriate information in their molecular building blocks. So far, supramolecular chemistry has made significant advances in constructing complex molecular machinery by self-assembly in organic media, but studies in aqueous media have lagged behind. There are still relatively few examples of discrete synthetic supramolecules based on small molecules held together solely with non-covalent interactions. There is a gap in the development of appropriate recognition motifs that are easy to make and offer robust and reliable self-recognition properties in aqueous environments. There is also a gap in the development of efficacious ligands that recognize G-quadruplex DNA (QDNA) with high specificity and affinity. We propose to fill these gaps by making small molecule guanine (G) derivatives (Aim 1) and studying their self-assembly in water (Aim 2). The usefulness of the resulting supramolecules will be highlighted by their use as self-assembled ligands (SALs) for the specific recognition of QDNA (Aim 3). QDNA is the subject of intense studies due to its putative role in telomere function and in the regulation of some oncogenes. The ensuing supramolecules should further our long-term goal of expanding nanomedicine's molecular 'toolbox'by developing better diagnostic probes and therapeutics.

Public Health Relevance

This project will enable the use of small molecules to construct well-defined and discrete self-assembled nanostructures in aqueous environments. These substances have a great potential for the development ligands for quadruplex DNA that could lead to novel therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Enhancement Award (SC1)
Project #
5SC1GM093994-04
Application #
8502696
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (CH))
Program Officer
Preusch, Peter C
Project Start
2010-07-26
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$315,225
Indirect Cost
$100,271
Name
University of Puerto Rico Rio Piedras
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
143960193
City
San Juan
State
PR
Country
United States
Zip Code
00931
Rivera, Jose M; Silva-Brenes, Diana (2013) A photoresponsive supramolecular G-quadruplex. Org Lett 15:2350-3
Negron, Luis M; Melendez-Contes, Yazmary; Rivera, Jose M (2013) Patchy supramolecules as versatile tools to probe hydrophobicity in nanoglobular systems. J Am Chem Soc 135:3815-7
Rivera, Luis R; Betancourt, Jose E; Rivera, Jose M (2011) Aquatic self-assembly of sixteen subunits into a 39-kDa dendrimer. Langmuir 27:1409-14
Martin-Hidalgo, Mariana; Rivera, Jose M (2011) Metallo-responsive switching between hexadecameric and octameric supramolecular G-quadruplexes. Chem Commun (Camb) 47:12485-7
Betancourt, Jose E; Subramani, Chandramouleeswaran; Serrano-Velez, Jose L et al. (2010) Drug encapsulation within self-assembled microglobules formed by thermoresponsive supramolecules. Chem Commun (Camb) 46:8537-9