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Maria Contel, Guillermo Gerona-Navarro, Brian Gibney, Alexander Greer, Ankit Jain, Aneta Mieszawska, Ryan Murelli
Maria Contel, Lesley Davenport, Terry Dowd, Emilio Gallicchio, Guillermo Gerona-Navarro, Brian Gibney, Laura Juszczak, Aneta Mieszawska, Mariana Torrente
Emilio Gallicchio, Andrzej Jarzecki, Laura Juszczak, Mark Kobrak
The Department of Chemistry hosts the Interdisciplinary Computation and Modeling research Program for Undergraduate students (ICoMPUte) funded by the National Science Foundation, in which students work in interdisciplinary teams on projects involving wet lab experiments as well as molecular simulations.
Participating Chemistry faculty: Maria Contel, Terry Dowd, Emilio Gallicchio, Aneta Mieszawska, Ryan Murelli, Mariana Torrente
Our faculty is engaged in collaborative research with other departments and medical research institutes to help discover the novel drug therapies to treat cancer and are members of the Brooklyn College Cancer Center BCCC-CURE.
Participating Chemistry faculty: Maria Contel, Lesley Davenport, Terry Dowd, Emilio Gallicchio, Brian Gibney, Alexander Greer, Guillermo Gerona-Navarro, Aneta Mieszawska, Ryan Murelli, Mariana Torrente
Interested in doing research with one of our faculty members? Check their profiles below and contact them.
Organometallic Chemistry and Medicinal Chemistry
Our laboratory focuses on the design of metal-based compounds with applications in medicinal chemistry and homogeneous catalysis. We synthesize compounds based mostly on gold, ruthenium, and titanium (mono and heterometallic) to study their potential as anticancer and antimicrobial agents. We study their biological activity in vitro and in vivo as well as their modes of action. We design strategies to deliver anticancer agents more efficiently, and to preferentially target tumors to improve their pharmacological profile. These strategies involve the use of functionalized nanocarriers and monoclonal antibodies as delivery vehicles. Catalytic studies focus on recyclable and bimetallic catalysts and on sustainable processes. Our work is interdisciplinary in nature and our research spans the fields of organometallic chemistry, nanotechnology, and the biochemistry and biology of cancer and infectious diseases. We have very productive collaborations with researchers at CUNY, and at different medical centers and universities in New York, the United States, and overseas. We have been funded by the National Institutes of Health since 2010. We are committed to the incorporation of researchers from underrepresented groups in the physical sciences to our group.
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Biochemistry and Biophysics
Our research focuses on studying the conformation and dynamics of important biomolecules, including DNA and proteins using optical spectroscopic methods such as fluorescence and circular dichroism. These biophysical measurements can help to understand the relationship between biochemical function and conformation and dynamics at the molecular level. Currently we are investigating the folding of guanine-rich DNA sequences into four-stranded G-quadruplexed “knot” structures, which are found both within human telomeric DNA, and more recently within genomic DNA. We are particularly interested in the promotion of folded telomeric quadruplexed DNA conformations through the binding of small organic molecules. Such ligands can serve as potential chemotherapeutics, since telomeric DNA “knots” have been shown to serve as inhibitors of telomerase, a key enzyme in tumorigenesis. Other projects involve studies of the folding pathway for plasma amine oxidase, a complex oligomeric protein that has implications in heart disease.
The Role of Osteocalcin in Normal and Diseased Bone
Bone fracture and osteoporosis are major health problems affecting the elderly and observed in certain diseases and bone disorders such as magnesium deficiency, Type I and Type II diabetes and in elevated blood lead levels. My research involves investigating the mechanisms which contribute to weakened bone. One mechanism of interest involves the role of noncollagenous bone proteins in bone disease and fracture. A protein of interest is osteocalcin (5850 MW), one of the most abundant noncollagenous proteins in bone. Several studies have provided a role for osteocalcin in bone remodeling, enhancing mineral deposition, regulating crystal morphology, and increasing bone toughness and fracture resistance. Osteocalcin is decreased in bone with age and in some diseases such as diabetes where bone fracture is prevalent. To obtain more mechanistic information on bone fracture in disease and mineral disorders we study bones from wild-type (w/osteocalcin) and osteocalcin depleted knock-out mice exposed to different conditions (low and normal Mg diets, low Pb2+ levels, etc). We investigate bone mineral properties with FTIR Imaging, microCT imaging, bone turnover Elisa assays, Atomic Absorption and biomechanical tests for bone strength. Data from different mineral sets are compared and information on the role of osteocalcin in bone impairments is obtained. We also look at other protein knock-out mice and diabetic mineral with these techniques. The information collected contributes to the etiology of bone disorders and is relevant to new therapeutic approaches for bone fracture.
Molecular Modeling
Gallicchio’s lab develops theoretical models and high-performance computing software to model chemical and biological processes. The current focus of the lab is the use of atomistic molecular dynamics simulations on GPUs and statistical inference to predict the affinities of drugs to target protein receptors. These tools are used to screen chemical compounds on computers before they are synthesized, and to guide the optimization of drugs to improve their selectivity and efficacy. The lab collaborates with medicinal chemistry laboratories at CUNY and elsewhere to help develop therapies for cancer, viral infections, and drug addiction among others. Our research interests are highly interdisciplinary spanning topics from biochemistry, physics, statistical mechanics, and computer science.
A cell-penetrating bis-thioether stapled peptide inhibits H3K27me3, an epigenetic modification strongly associated with development of multiple human cancers.
Protein-Protein Interactions (PPIs) are instrumental in the regulation of biological processes and hence they are involved in the development and progression of human diseases. Modulating PPIs remains a challenging task for medicinal chemists due to the “undruggable” nature of such recognition events, which take place through large, featureless protein surfaces that are usually unfit for small molecules ligands. Our laboratory aims to address this problem by developing peptidomimetic molecules, such as bisthioether stapled peptides, capable of effectively disrupting biologically relevant intracellular PPIs in an allosteric fashion. In particular, we are interested in targeting epigenetic molecular mechanisms that have been shown to play a key role in the development and progression of multiple human cancers. Our chemical biology research encompasses the design, synthesis and biological evaluation of peptidomimetics with potential application in epigenetic cancer therapies and cover a broad range of chemistry, biochemistry and molecular biology techniques. Our ultimate goal is to contribute to a better understanding of the chromatin effect and its impact in re-programming the epigenome in cancer, and more importantly, to develop new molecular therapeutics.
Organic Chemistry and Photochemistry
Our group utilizes both experimental and theoretical methods to research fundamental aspects of organic photochemistry. Our main focus is controlling and amplifying the production of reactive oxygen species. Our current projects involve organic oxidation mechanisms, visible-light photosensitization, reactive intermediates, and photo-reactor development. We also study the interfacial behavior of reactive oxygen species, including singlet oxygen and alkoxy radicals. Our fundamental research is connected to applied research in the area of photodynamic therapy.
Quantum-Mechanical Studies of Biomolecules
Our research is based on computational modeling of the interaction of metals with biomolecules using quantum-mechanical methods. Our aim is molecular and spectroscopic properties of transition and heavy metals to understand how the molecular structure of the chelating ligands relates to the biochemical storage, transport, and delivery of metals or their diatomic ligands such as O2, CO, or NO. This could have important implications for the development of novel bio metallic therapeutic agents. In parallel with these efforts, our laboratory is investigating highly toxic metals, including lead, cadmium, and mercury. Their toxicity is believed to stem from its strong affinity for binding sulfur, oxygen, and nitrogen. This affinity, combined with metal’s unique coordination preferences, disrupt protein structures and prevent their function. Most organisms have no defense against these metals but a few species demonstrate resistance to its toxic effects. We seek to understand this phenomenon.
The photophysics of cation- interactions
Our recent work has shown that cation-π interactions—between an aromatic molecule and an apositioned cation—are not merely electrostatic in nature; aromatic electron density is transferred to the cation, lending a radical character to the aromatic. Unexpectedly, this results in visible absorption and fluorescence from the cation-π complex. Because these interactions play a key role in many biological scenarios—the binding of ligands to acetylcholine receptors and the interaction of reader proteins with histone tail methylated lysines, to name only a couple—understanding the subtle effects of the myriad possible combinations of aromatics and cationic ligands on their spectroscopy becomes a useful tool for drug development and for organic (bio)electronics. This is the subject of our work.
Physical Chemical Studies of Nanostructured Liquids and Nanoscale Interfaces
We use theoretical and experimental methods to study the properties of liquids and interfaces. Our work considers fundamental questions related to liquid structure and the behavior of solvents as well as applied problems such as the extraction of toxic or valuable metals from water. Key to this work is the connection of basic physics to emergent chemical properties such as hydrophobicity and solvent polarity.
Nanomedicine
We develop multifunctional nanoparticle systems for drug delivery and biomedical applications. Our focus is on cancer therapy and the use of nanoparticles to alleviate the side effects of conventional chemotherapy and improve the therapeutic outcomes. We work with biodegradable and biocompatible hybrid nanoparticles based on polymers, lipids and peptides to produce nanotherapy responsive to tumor’s microenvironment. Our current projects involve peptide-stabilized nanoparticles for active targeting of receptors overexpressed on cancer cells, angiogenesis targeting, and theranostics-concurrent therapy and imaging. Related area of interest is the development of nanoparticles for drug delivery into specific organelles to increase therapeutic effects.
Synthetic Organic Chemistry and Medicinal Chemistry
Research in the Murelli lab is aimed at making fundamental contributions to synthetic organic chemistry, biology and medicine. To accomplish this, they seek out problems in medicinal chemistry and chemical biology that are in need of new synthetic organic chemistry developments. Thus, primary studies carried out by lab members range from reaction discovery and mechanism investigations to multi-step synthetic strategy developments. The group simultaneously partners with experts in complementary fields in order to leverage their advancements in a broad range of interdisciplinary projects devoted to lead drug discovery and development. The lab is particularly interested in the synthesis and biology of highly oxygenated troponoids, which have a wealth of biological activity and potential as lead drugs fragments.
Figure adapted from “Neurodegenerative Disease Proteinopathies Are Connected to Distinct Histone Post-translational Modification Landscapes” by Karen Chen, Seth A. Bennett, Navin Rana, Huda Yousuf, Mohamed Said, Sadiqa Taaseen, Natalie Mendo, Steven M. Meltser, and Mariana P. Torrente, ACS Chemical Neuroscience 2018 9 (4), 838-848
ALS is a progressive neurodegenerative disease that affects both lower motor neurons in the brainstem and spinal cord, and the upper motor neurons in the motor cortex. No cure is available for ALS, and current treatments fail to control symptoms.
ALS is classified into two categories: familial and sporadic ALS, both of which present with similar clinical symptoms; familial ALS represents 5 to 10% of cases. Familial ALS has been linked to mutations in 40 different genes. How can so many genes—involving many distinct cellular functions—produce the same symptomatology? And how can we treat a disease with so many apparent molecular causes? Could there be a role for epigenetics in the etiology of ALS?
Eukaryotic DNA is packaged into chromatin, a highly organized protein-DNA complex. Changes in the composition and structure of chromatin are sufficient to cause heritable phenotypic changes. These changes are termed epigenetic. Epigenetics determines whether, when, and how particular genes will be transcribed.
The basic unit of chromatin is the nucleosome, which consists of DNA wrapped around a histone core. The N-terminal “tails” of histones project out of the nucleosome core. The protruding histone tails are decorated with various post-translational modifications (PTMs) including chemical moieties such as phosphorylation, methylation, and acetylation. These modifications regulate access to genetic information.
We hypothesize that epigenetic mechanisms—namely histone modifications—play a pivotal role in the neuronal death characterizing ALS. Our lab studies the histone modification profiles relating to ALS in several model systems using both immunoblotting and proteomic methods. We are grateful for funding from the NINDS K22 Transition to Independence Program.
