Research Description

Development of Novel Molecules and Devices to Measure Biological Activity

The overarching theme of our research program is the development of novel molecules and devices enabling biological activities to be measured in new ways.  The projects underway involve aspects of diverse disciplines ranging from biomolecular chemistry, molecular biology, and cell biology to materials science, biomedical engineering and nanotechnology.

Mitochondrial Chemical Biology

Mitochondria are very interesting compartments within the eukaryotic cell with a unique evolutionary history.  The bacterial origin of mitochondria and retention of a genome differentiate this organelle from others within the cell.  Because of the impermeable nature of the mitochondrial membranes, genetic manipulation of the mitochondrial is difficult and as a result little is know about the processes within the organelle that involve nucleic acids. We recently developed a peptide-based delivery vector that can carry reactive cargo into the mitochondria of live mammalian cells.  By attaching agents that generate reactive oxygen species or alkylation damage, we can site-specifically probe the cellular response to these insults and deconvolute this response from that resulting from nuclear damage.  This approach is revealing new insights into how mitochondrial DNA damage is responded to, and has also indicated that the makeup of mitochondria make them susceptible to other types of bimolecular damage.

Peptide Vectors for Intracellular Targeting

Controlling the intracellular localization of synthetic molecules is essential for effective drug development. Nonetheless, rational control over intracellular trafficking of small molecules has remained a challenge. The Kelley lab has engineered peptide-based conjugates to deduce rules for manipulating intracellular localization of bioactive molecules. These compounds also provide useful tools for the cellular delivery of chemically or biologically active species and can be used to study organelle-specific processes. We have used these vectors to delivery a variety of bioactive cargo to mitochondria.  Clinically-utilized anticancer drugs that typically act within the nucleus have been shown to have interesting activities when delivered to mitochondria, and we have also developed a strategy to detoxify antimicrobials within human cells by sequestering the drugs within this organelle.

Biotemplated Materials

The worlds of biology and semiconductor engineering have traditionally been quite distinct. The spontaneous assembly of biological materials presents a stark contrast to the rational fabrication required for high performance semiconductors. The merger of these diverse materials represents a tremendous opportunity, given that biomolecules can organize into intricate, functionally sophisticated structures exactly the sort of precise, elegant control urgently needed to make the next generation of materials for computing, communications, energy, and the environment. Thus, we are using biomolecular templates – particularly nucleic-acids based scaffolds – for the synthesis of semiconductor nanocrystals. We have demonstrated that rational programming of the size and luminescence spectra of colloidal quantum dot nanocrystals is possible through the choice of nucleotide ligands responsible for nanoparticle nucleation, growth, stabilization, and passivation. Moreover, we have shown that nucleic acid conformation can be used to modulate structures of nanocrystals, and that complex three-dimensional structures can be assembled.  The results obtained thus far point the way to programmable synthesis of nanoparticles using precisely-controlled polynucleotide sequences.

Ultrasensitive Biomolecular Detection

Advances in genomic and proteomic methods now allow classification of disease based on molecular profiling. The detection of a molecular analytes and use of this type of information for disease diagnosis requires methods with superior sensitivity and specificity, along with high-throughput. We are developing new analytical methods with these properties that will permit the direct readout of nucleic acid sequences and protein biomarkers. Novel technologies for ultrasensitive DNA, RNA, and protein sensing have been developed in our laboratories that use electrochemical methods for readout. Chip-based sensors made from nanomaterials play an important role in this effort, as detection sensitivity is greatly enhanced when measurements are performed at the nanoscale. We have also recently developed devices that capture rare cells with high efficiency.  Our aim is to generate detection systems applicable to the diagnosis of cancer, infectious disease and other disease states. Members of this project team fabricate devices, develop reporter assays and work with biological and clinical samples to validate new technologies. Substantial collaboration with engineers and clinical researchers is an important part of this project.

Publications

View all publications on PubMed

Highly Specific Electrochemical Analysis of Cancer Cells using Multi-Nanoparticle Labeling.
Wan Y, Zhou YG, Poudineh M, Safaei TS, Mohamadi RM, Sargent EH, Kelley SO.
Angew Chem Int Ed Engl. 2014  Read

Structural modifications of mitochondria-targeted chlorambucil alter cell death mechanism but preserve MDR evasion.
Jean SR, Pereira MP, Kelley SO
Mol Pharm. 2014 11(8):2675-82  Read

Targeting mitochondrial DNA with a platinum-based anticancer agent.
Wisnovsky SP, Wilson JJ, Radford RJ, Pereira MP, Chan MR, Laposa RR, Lippard SJ, Kelley SO.
Chem Biol. 2013 20(11):1323-8  Read

Tuning the intracellular bacterial targeting of peptidic vectors.
Lei EK, Pereira MP, Kelley SO
Angew Chem Int Ed Engl. 2013 52(37):9660-3  Read

Targeted delivery of doxorubicin to mitochondria
Chamberlain GR, Tulumello DV, Kelley SO
ACS Chem Biol. 2013 8(7):1389-95  Read

Solution-based circuits enable rapid and multiplexed pathogen detection.
Lam B, Das J, Holmes RD, Live L, Sage A, Sargent EH, Kelley SO.
Nat Commun. 2013 4:2001  Read

Maximizing the therapeutic window of an antimicrobial drug by imparting mitochondrial sequestration in human cells
Pereira MP, Kelley SO
J Am Chem Soc. 2011 133(10):3260-3  Read

Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells
Fonseca SB, Pereira MP, Mourtada R, Gronda M, Horton KL, Hurren R, Minden MD, Schimmer AD, Kelley SO
Chem Biol. 2011 18(4):445-53  Read

Programming the detection limits of biosensors through controlled nanostructuring
Soleymani L, Fang Z, Sargent EH, Kelley SO
Nat Nanotechnol. 2009 4(12):844-8  Read

Mitochondria-penetrating peptides.
Horton KL, Stewart KM, Fonseca SB, Guo Q, Kelley SO
Chem Biol. 2008 15(4):375-82  Read