Academic Appointments:

Dean, School of Natural and Behavioral Sciences, Brooklyn College, The City University of New York
Professor, Department of Biology, Brooklyn College, The City University of New York

Degree
Ph.D. (Microbiology and Immunology), McGill University, Canada

Research Focus:

My research team has focused on understanding the biochemistry of the Mitogen Activated Protein Kinase (MAPK) Signaling pathway and its role in cancer by developing and using drugs that can therapeutically modulate this biochemical pathway. The signaling that occurs within this pathway is extremely important as it controls many essential cellular functions such as cytoskeleton organization, aging and programed cell death, calcium signaling, trafficking of vesicles, and cellular proliferation/cell division. Proliferation of cells is a critical component of the MAPK pathway because when perturbed leads to many different types of solid tumors as well as blood cancers. To date, only two proteins, BRAF and MEK. that function in the MAPK pathway have been successful targeted with available FDA approved drugs. The problem with all currently approved drugs against these two targets is that patients develop resistance to the therapeutic effects of these drugs within two years and the caner returns, hence the need to develop new drugs against other targets in the MAPK pathway. At the top of the MAPK pathway are the products of the RAS gene which are among the highest priority drug targets in oncology. This gene is mutated, causing it to be hyperactive, in 30% of all human tumors including 90% of pancreatic, 45% of colon and 35% of lung cancers. Cancers with KRAS mutations are aggressive and respond poorly to standard untargeted chemotherapies.

We have used computational modeling (supercomputing) of the mutated KRAS protein based on published X-ray crystallography data to determine areas that a drug can possibly bind as well as computational chemistry of compounds developed by others that have failed to effectively modulate the pathway. This metanalysis has led us to many new ideas of how to develop new candidate compounds. We then used medicinal organic chemistry to develop these new drug candidates against KRAS and proceeded to accesses them in biochemical assays. After numerous failures, a compound was synthesized with low but reproducible (in triplicate) biochemical inhibition (12%) of the hyperactive KRAS G12C mutant. We have also designed and synthesized a novel analogue of this compound in an effort to significantly enhance its potency.

Computational modeling (supercomputing) of the mutated KRAS protein was also used based on published X-ray crystallography data to determine areas that a drug can possibly bind as well as computational chemistry of compounds developed by others that have failed to effectively modulate the pathway. This metanalysis has led us to many new ideas of how to develop new candidate compounds. We then used medicinal organic chemistry to develop these new drug candidates against KRAS and proceeded to accesses them in biochemical assays. After numerous failures, a compound was synthesized with low but reproducible (in triplicate) biochemical inhibition (12%) of the hyperactive KRAS G12C mutant. We have also designed and synthesized a novel analogue of this compound in an effort to significantly enhance its potency.

A second target that we have pursued is the SOS protein which physically interacts with RAS and controls it’s GTPase activity and subsequent signaling. We studied the 3D X-ray structure of this interaction from publicly available data banks and identified a contact point that had a groove in SOS that we believed may offer a new target site to develop compounds that would inhibit the interaction in biochemical assays. We then proceeded to use computational modeling on a supercomputer and identified theoretical compounds that fit in this groove out of 11 million possible structures using high throughput docking at this junction site. Three of these compounds (out of the 103 that were identified by computational modeling) were confirmed biochemically with low micromolar potency and share a common scaffold. We are currently designing and synthesizing novel analogues of these compounds to significantly enhance their potency.

Our third target in the MAPK pathway is ERK which is the last key protein involved in the signaling cascade. A drug against ERK would create a new effective first line treatment for melanoma, colon and pancreatic cancer and new hope for patients with BRAF and MEK resistant tumors. We have spent most of our effort on this target and have been able to push our progress to a significant milestone. Our approach was similar to what was done in the RAS project described earlier in that we used computational modeling (supercomputing) of the ERK protein based on published X-ray crystallography data to determine areas that a drug can possibly bind as well as computational chemistry of compounds developed by others that have failed to effectively modulate the pathway. We then used medicinal chemistry in an attempt to develop a novel, potent, selective, orally efficacious ERK inhibitor. Fortuitously, one of the candidate compounds that we synthesized early in our efforts was able to inhibit ERK in a biochemical assay with excellent potency.

Through multiple cycles of computational refinement, organic chemistry synthesis and biochemical assessment, we have identified a very potent compound in the low nanomolar range
We will continue to use computational and medicinal chemistry to make all of our lead compounds more potent and file patents on refined structures as well. We are also testing these compounds in secondary biochemical assays, in cell-based assays and will ultimately develop a mouse animal model for testing. In summary, the compounds we are pursuing may serve as the foundation of new FDA approved therapeutics against a variety of cancers targeting three distinct components of the MAPK signaling pathway.

Selected Publications

• Haoshuang Zhao, Michael Sabio, Sid Topiol, Kuo-Sen Huang, Naoko Tanaka, Wei Chu, Ueli Gubler, Peter Tolias (2020). A Novel Strategy for Identifying Non-covalent KRas Inhibitors: Design and Biochemical Characterization of KRas(G12C) Double Mutants for Compound Screening. Medical Research Archives. Vol 8, Issue 6. https://doi.org/10.18103/mra.v8i6
• Lotfaliansaremi, S., Sabio, M., Cornwell, S., and Tolias, P. (2020). Role of the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Cancer. Medical Research Archives. Vol 8, Issue 4. DOI:https://doi.org/10.18103/mra.v8i4
• Agresti, C.A., Halkiadakis, P.N. and Tolias, P. (2018). MERRF and MELAS: Current Gene Therapy Trends and Approaches. J Transl Genet Genom 2018;2:9. http://dx.doi.org/10.20517/jtgg.2018.05
•  Wilson, C and Tolias, P. (2016). Recent Advances in Cancer Drug Discovery Targeting RAS. Drug Discovery Today, 21 (12), 1915-1919. http://dx.doi.org/10.1016/j.drudis.2016.08.002

Patents

• W. Lee, J. Zilberberg, D.S. Siegel, P. Tolias, H. Wang, W. Zhang (2019). Ex Vivo Human Multiple Myeloma Cancer Niche And Its Use As A Model For Personalized Treatment Of Multiple Myeloma. Patent #10,184,113
• W. Lee, J. Zilberberg, D.S. Siegel, P. Tolias, H. Wang, W. Zhang (2016). Ex Vivo Human Multiple Myeloma Cancer Niche And Its Use As A Model For Personalized Treatment Of Multiple Myeloma. Patent # 9,267,938
• T. Chang, P. Tolias (2006). Delivery of Metered Amounts of Liquid Materials. Patent # 7,097,810

Grants over the last 5 years

• $30,000 (2/1/20-1/31/21) from Olipass Corporation. Thermodynamic and Kinetic Characterization of Oligonucleotide Association
• $1,732,659 (10/1/15-9/30/22) from Cepter Biopartners. DNA cloning, expression and purification of therapeutic proteins, assay development and drug screening
• $46,800 (2/1/15-12/31/15) from M1T Capital Partners. Development of kiosk interfaces for transferring electronic medical records to service providers
•  $10,000 (1/1/15-12/31/15) from Pfizer Undergraduate Research Endeavors. Structural analysis of hepatitis B virus X protein (HBx) and human host cell protein DNA damage binding protein 1 (DDB1).

• Tel: 718.951.3170
• Location: Ingersoll Hall, Room 2131
• Website: Link

Academic Appointments:

2020-present   Joint Appointment, PhD Program in Biochemistry, Graduate Center of CUNY
2019-present   Professor, Department of Chemistry, Brooklyn College
2017-2019       Associate Professor, Department of Chemistry, Brooklyn College
2017-present  Organic Sub-discipline Chair in PhD Program in Chemistry
2010-present   Joint Appointment, PhD Program in Chemistry, Graduate Center of CUNY
2010-2017      Assistant Professor, Department of Chemistry, Brooklyn College

Degrees:

BA      Chemistry                               Hamilton College, Clinton, NY
PhD     Organic Chemistry              Boston College, Chestnut Hill, MA

Research Focus:

Our group is a synthetic organic chemistry lab whose members develop organic reactions and multistep synthetic strategies towards various molecular targets, and then use these strategies in a broad range of projects that represent both fundamental and translational research.  Two distinct but complementary research niches have emerged from our synthetic organic chemistry work to date based around developing and exploiting oxidopyrylium [5+2] cycloaddition reactions, as well as developing new synthetic strategies to access tropone-containing molecules.  These studies have been particularly valuable in accessing a class of metalloenzyme-binding fragments called 7-hydroxytropolones (or a-hydroxytropolones, which we often abbreviate as aHTs).  Our work on aHTs has led to dozens of collaborations from labs all around the world, which have allowed us to study this chemotype in depth.  Our most active collaborative network, which includes BC colleague Emilio Gallicchio as well as scientists from the National Cancer Institute and Saint Louis University School of Medicine, is interested in studying and optimizing aHTs as inhibitors of viral nuclease enzymes and the impact of this inhibition on antiviral activity against several viruses including HIV and herpes simplex virus, as well as the oncoviruses hepatitis B virus and Kaposi’s sarcoma-associated herpesvirus.  Repurposing efforts have also led to inroads against other pathogens such as Cryptococcus neoformans, the major causative agent of fungal meningitis worldwide.

Selected Publications:

1. Li, Q.; Lomonosova, E.; Donlin, M. J.; Cao, F.; O’Dea, A.; Milleson, B.; Berkowitz, A. J.; Baucom, J-C.; Stasiak, J. P.;Schiavone, D. V.; Abdelmessih, R. G.; Lyubimova, A.; Fraboni, A. J.; Bejcek, L.P.; Villa, J. A.; Gallicchio, E.; Murelli, R. P.*; Tavis, J. E.* “Amide-containing α-hydroxytropolones as inhibitors of hepatitis B virus replication” Antiviral Res. 2020, 177, 104777.
2. Agyemang, N. B.; Kukla, C. R.; Edwards, T. C.; Li, Q.; Langen, M. K.; Schaal, A.; Franson, A. D.; Gazquez Casals, A.; Donald, K. A.; Yu, A. J.; Donlin, M. J.; Morrison, L. A.; Tavis, J. E.; Murelli, R. P.* “Divergent Synthesis of a Thiolate-Based α-Hydroxytropolone Library with a Dynamic Bioactivity Profile” RSC Advances, 2019, 9, 34227.
3. Hirsch, D. R.; Schiavone, D. V.; Berkowitz, A. J.; Morrison, L. A.; Masaoka, T.; Wilson, J. A.; Lomonosova, E.; Zhao, H.; Patel, B. S.; Dalta, S. H.; Majidi, S. J.; Pal, R.; K.; Gallicchio, E.; Tang, L.; Tavis, J. E.; Le Grice, S. F. J.; Beutler, J. A.; Murelli, R. P.* “Synthesis and Biological Assessment of 3,7-Dihydroxytropolones” Biomol. Chem. 2018, 16, 62-69
4. Miller, J. T.; Zhao, H.; Masaoka, T.; Varnado, B.; Cornejo Castro, E. M.; Marshall, V. A.; Kouhestani, K.; Lynn, A. Y.; Aron, K. E.; Xia, A.; Beutler, J. A.; Hirsch, D. R.**; Tang, L.; Whitby, D.; Murelli, R. P.; Le Grice, S. F. J.* “Sensitivity of the C-Terminal Nuclease Domain of Kaposi’s Sarcoma-Associated Herpesvirus ORF29 to Two Classes of Active Site Ligands” Agents. Chemother. 2018, 62, e00233-18.
5. D’Erasmo, M. P.; Murelli, R. P.* “Fluorous-Phase Approach to α-Hydroxtropolone Synthesis” Org. Chem. 2018, 83, 1478.

Patent Applications:

3. Donlin, M. J.; Tavis, J. E.; Murelli, R.; Meyers, M. J. “Preparation of substituted cycloheptatrienones as antifungal compounds” PCT Int. Appli. (2017) No. WO 2017-184752.
4. Tavis, J. E; Morrison, L. A.; Murelli, R. P. “Preparation of hydroxylated tropolone inhibitorsof nucleotidyl transferases in treatment of herpesvirus and hepatitis B” PCT Int. Appl. (2016) No. WO 2016-201243.
5. Spiegel, D.; Murelli, R.; Zhang, A. “Chimeric Small Molecules that Recruit Antibodies to Cancer Cells” PCT Int. Appl. (2009) No. WO 2009-US2857.  Patent No. WO  2009139863.

Active Research Support: 

(May 2020 – Apr. 2024) National Institutes of Health, NIGMS (SC1)  “Development and Exploitation of New Synthetic Strategies for Tropolones ” ($1,533,665.00) Role: PI

(Dec. 2015 – Nov. 2020) National Institutes of Health, NIAID (RO1) “Optimization of alpha-hydroxytropolones as novel inhibitors of the HBV RNaseH” ($658,553 of $2,740,000) [PI, John Tavis] Role: Collaborator under subcontract

Completed Research Support:

(Apr. 2015 – May 2020) National Institutes of Health, NIGMS (SC1) “Synthetic and biological studies of α-Hydroxytropolones”($1,558,600)

(July 2012 – July 2013) PSC CUNY Program (65420-00 42) “Synthesis of 7-hydroxytropolones” ($3,500) Role: PI

(Apr. 2012 – Nov. 2015) National Institutes of Health, NIGMS (SC2) “Synthetic and biological studies of antitubercular natural products” ($471,000) Role: PI

(March 2015 – February 2016) Alfred P. Sloan Foundation CUNY Junior Faculty Award in Science and Engineering ($50,000)

• Tel: 1.718.951.5000 ext. 2821
• Website: Link

Academic Appointments:

Associate Professor, Chemistry Department, Brooklyn College, The City University of New York
Faculty, Chemistry, Biology and Biochemistry PhD Programs, The Graduate Center, The City University of New York

Degree(s)

Ph.D. (Chemistry) University of Louisville, KY, USA

Research Focus:

My research interests span across nanotechnology and nanomedicine with specific interest in designing and testing the theranostic nanoparticle systems, as well as bioconjugates for concurrent imaging and therapy of disease. We focus on formulating the nanoparticles for cancer therapy. The development of multifunctional nanoparticle-based platforms with targeting, drug loading, and imaging features offer better treatment/imaging efficiencies than free drugs or traditional imaging agents. This involves formulation of theranostic nanoparticles based on poly(lactic-co-glycolic acid) (PLGA) or oil-in-water nanoemulsions. The nanoparticle-based formulations or bioconjugation offer lower toxicity profiles for many drug molecules, long in vivo circulation, and sustained release. We focus primarily on producing nanoparticle-based and peptide-based delivery methods for highly potent but also highly toxic chemotherapy agents e.g. platinum (II). We have synthesized new Pt (II) complexes with functional groups available for click chemistry, which gives an option to attach Pt (II) to other supports, such as biological carriers, polymers or oils. We have developed the Pt (II)-nuclear localization sequence peptide hybrid that shuttles Pt (II) directly into the nucleus. This led to dramatic improvements in Pt (II) delivery to the nucleus and higher cytotoxicity towards cancer cells. We have also prepared lipophilic nanoparticle formulations of Pt (II) stabilized with tripeptide KYF. The nanoemulsion showed superior biological activity when compared to free drug. The latter was an important proof-of-concept study demonstrating, for the first time, peptide stabilization of a nanostructure. Currently, we continue our research on peptide-stabilized nanoparticles exploring other materials, such as PLGA polymers as a nanoparticle’s core. We included combretastatin A4 (CA4), the tubulin-binding vascular disrupting agent, in the formulation. We found that the RGDFFF-coated nanoparticles combined with the CA4 were biologically active against angiogenic and cancer cells, and they effectively targeted tumors in vivo. Importantly, other targeting peptides could be easily included in the nanoparticle formulation, thus facilitating multi-receptor targeting approaches. In addition, we formulate nanoparticles with an array of small drug molecules that have different mechanisms of action, e.g. targeting mitochondria. This highlights our interest in pursuing the next generation nanoparticles, which are capable of targeted drug delivery to organelles in cancer cells.

Selected Publications

Dragulska, SA, Wlodarczyk, MT, Poursharifi, M, Mieszawska, AJ, “Engineering of a tripeptide-stabilized nanoemulsion of oleic acid for biological imaging and drug delivery applications.” R JOVE 2019.

Dragulska, SA, Chen, Y, Wlodarczyk, MT, Poursharifi, M, Dottino, P, Ulijn, RV, Martignetti, JA, Mieszawska, AJ, “Tripeptide-stabilized oil-in-water nanoemulsions of an oleic acid-platinum (II) conjugate as an anticancer nanomedicine.” R Bioconjugate Chem. 2018, PMID 30001618.

Wlodarczyk, MT, Dragulska, SA, Camacho-Vanegas, O, Dottino, PR, Jarzecki, AA, Martignetti, JA, Mieszawska, AJ, “Platinum (II) complex – nuclear localization sequence peptide hybrid for overcoming platinum resistance in cancer therapy” R ACS Biomater. Sci. Eng. 2018, 4, 2, 463-467.

Duivenvoorden R, Tang J, Cormode DP, Mieszawska AJ, Izquierdo-Garcia D, Ozcan C, Otten MJ, Zaidi N, Lobatto ME, van Rijs SM, Priem B, Kuan EL, Martel C, Hewing B, Sager H, Nahrendorf M, Randolph GJ, Stroes ES, Fuster V, Fisher EA, Fayad ZA, Mulder WJ, “A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation” Nat. Commun. 2014, PMID 24445279.

Patents

Aneta J. Mieszawska et al. Patent pending 20A0022: Peptide-stabilized poly(lactic-co-glycolic) acid nanoparticles US Patent 9,555,049 B2 (01/31/2017).

Grants over the last 5 years

Mieszawska, AJ, PI
NIH/NCI
R01CA238539
Anti-vascular and cytotoxic nanoparticle formulations for ovarian cancer therapy.
08/2019-07/2024

• Tel: 1.718.951.5000 ext. 2839
• Website: Link

Academic Appointments:

Professor of Chemistry, Brooklyn College of CUNY
Professor of Chemistry, The Graduate Center of CUNY

Degrees:

BS California State University, Chico; Ph.D. Chemistry, U. Wyoming

Research Focus:

Our group utilizes both experimental and theoretical methods to research fundamental aspects of organic chemistry and photochemistry. We are eager to accept researchers from various backgrounds, including nanotechnology, biochemistry, and even engineering. Our main focus is controlling and amplifying the production of reactive oxygen species. Our current projects involve organic oxidation mechanisms, visible-light photosensitization, secondary photosensitization, latent reactions following photooxidation, and photochemical-device development. One research area involves the use of fiber optics combined with sensitizer drugs for the production and precise delivery of singlet oxygen to eradicate cancer cells. This technique is referred to as “point-source” photodynamic therapy (i.e., PSPDT), delivers oxygen and red diode laser light through a device tip directed at the tumor site. This device helps avoid damage to healthy cells by focusing the sensitizer drugs and laser light within the tumor site. We also study the interfacial behavior of reactive oxygen species, including radicals at nanoparticle interfaces, and also the delivery of alkoxy radicals and singlet oxygen both as individual or tandem disinfectants. As mentioned above, secondary reactions are of interest to us. For example, the deconvolution of competitive light and dark processes is us offering insight into a priming mechanisms, including singlet oxygen priming as distinct from photodynamic priming. We are also using density functional theory and ab initio calculations which guide and deepen our understanding of experiments. Our work is currently funded by the National Science Foundation.

Selected Publications

C. C. Tonon; Xu, Q.; Ghosh, G.; S Ashraf; A. Nara de Sousa Rastelli; T. Hasan; A. Greer; A. L. Lyons “Evaluation of Photosensitizer-Containing Superhydrophobic Surfaces for the Antibacterial Treatment of Periodontal Biofilms” J. Photochem. Photobiol. B 2022, 112458.

B. Malek; W. Lu; P. P. Mohapatra; N. Walalawela^(a); S. Jabeen^(a); J. Liu; A. Greer “Probing the Transition State-to-Intermediate Continuum: Mechanistic Distinction Between a Dry vs Wet Perepoxide in the Singlet Oxygen ‘Ene’ Reaction at the Air-Water Interface” Langmuir 2022, 38, 6036-6048.

E. M. Greer; V. Siev; A. Segal; A. Greer; C. Doubleday “Computational Evidence for Tunneling and a Hidden Intermediate in the Biosynthesis of Tetrahydrocannabinol” J. Am. Chem. Soc. 2022, 144, 7646-7656.

Belh, S. J.^(a); Ghosh, G.; Greer, A. “Surface-Radical Mobility Test by a Self-Sorting Mechanism: Symmetrical Product upon Recombination (SPR)” J. Phys. Chem. B 2021, 125, 4212-4220.

A. M. Durantini; A. Greer “Interparticle Delivery and Detection of Volatile Singlet Oxygen at Air/solid Interfaces” Environ. Sci. Technol. 2021, 55, 3559-3567.

R. M. O’Connor^(c); A. Greer “How Tryptophan Oxidation Arises by ‘Dark’ Photoreactions from Chemiexcited Triplet Acetone” Photochem. Photobiol. 2021, 97, 456-459.

A. M. Durantini; P. P. Mohapatra; M. Ashaque^(c); M. E. Zatoulovski^(c); M. M. Kim; K. A. Cengel; T. M. Busch; T. C. Zhu; A. Greer “Photooxidative Vulnerability to Intralipid in Photodynamic Therapy” In Periodical Reports in Photochemistry of the Royal Society of Chemistry; Protti, S.; Raviola, C. Eds.; Cambridge, UK 2021, Vol. 48, pp. 411-422.

M. J. Sosa; M. N. Urrutia; P. L. Schilardi; M. I. Quindt; S. Bonesi; D. Denburg; M. Vignoni; A. Greer;E. M. Greer; A. H. Thomas “Mono– and Bis-Alkylated Lumazine Sensitizers: Synthetic, Molecular Orbital Theory, Nucleophilic Index, and Photochemical Studies” Photochem. Photobiol. 2021, 97, 80-90.

J. Robinson-Duggon; N. Pizarro; G. Gunther; D. Zúñiga-Núñez; A. M. Edwards; A. Greer; D. Fuentealba “Fatty Acid Conjugates of Toluidine Blue O as Amphiphilic Photosensitizers: Synthesis, Solubility, Photophysics, and Photochemical Properties” Photochem. Photobiol. 2021, 97, 71-79.

Matikonda, S. S.; Helmerich, D. A.; Meub, M.; Beliu, G.; Kollmannsberger, P.; Greer, A.; Sauer, M.; Schnermann, M. J. “Defining the Basis of Cyanine Phototruncation Enables a New Approach to Single Molecule Localization Microscopy” ACS Cent. Sci. 2021, 7, 1144-1155. Highlighted in C&E News.

M. S. Oliveira; G. Chorociejus; J. P. F. Angeli; G. M. V. V. Safadi; G. L. B. Aquino; G. E. Ronstein; L. F. Barbosa; M. C. Oliveira; M. H. G. Medeiros; A. Greer; P. Di Mascio “Heck Reaction Synthesis of Anthracene and Naphthalene Derivatives as Traps and Clean Chemical Sources of Singlet Molecular Oxygen in Biological Systems” Photochem. Photobiol. Sci. 2020, 19, 1590-1602.

O. Turque^(a); A. Greer; O. R. Wauchope “Synthetic Feasibility of Oxygen-driven Photoisomerizations of Alkenes and Polyenes” Org. Biomol. Chem. 2020, 18, 9181-9190.

S. Jabeen^(a); M. Farag^(c); B. Malek^(b); R. Choudhury; A. Greer A Singlet Oxygen Priming Mechanism: Disentangling of Photooxidative and Downstream Dark Effects. J. Org. Chem. 2020, 85, 12505-12513.

Ortel; S. Jabeen; A. Greer “Adjuvants that Empower the Action of Photodynamic Therapy” Photochem. Photobiol.2020, 96, 725-727.

Belh, S. J.; Walalawela, N.; Lekhtman,; Greer, A. “Dark-binding Process Relevant to Preventing Photooxidative Damage: Conformation Dependent Light and Dark Mechanisms by a Dual-functioning Diketone” ACS Omega 2019, 4, 22623-22631.

Walalawela; A. Greer “Heterogeneous Photocatalytic Deperoxidation with UV and Visible Light” J. Phys. Org. Chem.2018, e3807.

Malek; W. Fang; I. Abramova; N. Walalawela; A. A. Ghogare; A. Greer “Ene Reactions of Singlet Oxygen at the Air-Water Interface” J. Org. Chem. 2016, 81, 6395-6401.

A. Ghogare; A. Greer “Using Singlet Oxygen to Synthesize Natural Products and Drugs” Chem. Rev. 2016, 116, 9994-10034.

[(a) Ph.D. student; (b) MS student; (c) undergraduate student; (d) research assistant at Brooklyn College]

Patents

Lyons, A.M.; Greer, A.; Xu, Q.F., Singlet Oxygen Generating Device for Selective Destruction of Pathogens, US patent application No. 15/729005 Publication No. 20180099063, published 4/12/2018.

Grants over the last 5 years

External Federal Funding

NSF Single Investigator Award, 2022-2025

Mechanistic Organic Photochemistry: Dark Processes and Toxicity Priming

NSF STTR Phase I Award, 2021-2022, (for our company SingletO2 Therapeutics LLC with co-PI Marc Hodes, Tufts University)

Safe Disinfection and Oxygen-Level Enrichment in Recirculating Aquaculture Systems (RAS) Using Singlet Oxygen

NSF Single Investigator Award, 2019-2022,

Multiphase-Separation and Control of Serially Produced Reactive Oxygen

NIH SBIR Phase II Award, 2019-2022, (for our company SingletO2 Therapeutics LLC)

3D-Printed Superhydrophobic-Tipped Optical Fiber for Targeted Periodontal Photodynamic Therapy

• Tel: 1.718.951.5000 Ext. 2830
• Website: Link

Academic Appointments:

Associate Professor, Chemistry Department, Brooklyn College, The City University of New York
Faculty, Chemistry, Biology and Biochemistry PhD Programs, The Graduate Center, The City University of New York

Degree(s)

Instructor, Structural Biology Department, Mount Sinai School of Medicine NY, NY.
Postdoctoral Fellow, Structural Biology Department, Mount Sinai School of Medicine NY, NY.
Postdoctoral Fellow, Pharmacology Department. Weill Medical College of Cornell University, NY, NY.

Ph.D. (Chemistry, Cum Laude), Complutense University of Madrid (UCM), Madrid, Spain
B.S (Chemistry), University of Havana, Cuba

Research Focus:

Research in our laboratory encompasses a broad spectrum of bioorganic and synthetic chemistry in both solution and solid phase, together with a wide array of biochemical and cell assays. Development of small molecules and peptidomimetics targeting protein-protein interactions inside of the cell are being performed to investigate the role of these biologically important proteins in human biology and disease. In particular, we are focused on developing novel peptidomimetic molecules targeting epigenetic molecular mechanisms linked to development and progression of several types of cancers.

Our efforts to date has led to the identification of novel inhibitors of the catalytic activity of the Polycomb Repressive Complex 2 (PRC2), a multimeric complex of proteins responsible for the trimethylation of histone 3 at lysine 27 (H3K27me3), a repressive post-translational modification mark dysregulated in many different cancers. Our compounds target PRC2 allosterically. Their unique mechanism of PRC2 inhibition, together with their potency, remarkable H3K27me3 inhibition selectivity, and low cytotoxicity to non-cancerous cells suggest that they may have great potential for future development of novel epigenetic cancer therapies.

Selected Publications (last 5 years)

Rodriguez, Y.; Gerona-Navarro, G.; Osman, R.; Zhou, Ming-Ming. “In Silico Design and Molecular Basis for the Selectivity of Olinone Towards the First over the Second Bromodomain of BRD4” (R) Proteins 2020, 88 (3), 414-430. doi: 10.1002/prot.25818. [Epub 2019 Oct 21]

Pérez Gordillo, F. L.; Pérez de Vega, M. J.; Gerona-Navarro, G.; Rodríguez, Y.; Álvarez de la Rosa, D.; González Muñiz, R.; Martín-Martínez, M. “Aldosterone-Mineralocorticoid Receptor – Cell Biology to Translational Medicine,” 978-1-83962-199-4, 2019, Peer-Reviewed Book Chapter: Advances in the Development of non-steroidal mineralocorticoid-receptor antagonists. http://mts.intechopen.com/articles/show/title/advances-in-the-development-of-non-steroidal-mineralocorticoid-receptor-antagonists

Zhang, G.; Barragan, F.; Wilson, K.; Levy, N.; Herskovits, A.; Rodríguez, Y.; Sapozhnikov, M.; Kelmendi, L.; Alkasimi, H.; Korsmo, H.; Chouwdhury, M, Gerona-Navarro, G. “A Solid Phase Approach to Accessing Bisthioether Stapled Peptides Resulting in a Potent Inhibitor of PRC2 Catalytic Activity” (R) Angew. Chem. Int. Ed. Eng. 2018, 57, 17073

Zang, G.; Andersen, J.; Gerona-Navarro, G*. Peptidomimetics Targeting Protein-Protein Interactions for Therapeutic Development. (R, REV) Protein Pept. Lett. 2018, 25, 1076-1089

Gerona-Navarro*, G.; Zhang, G; Barragan. F. Bisthioether Stapled Peptides as Inhibitors of PRC2 Function. (US Provisional Patent Application, serial number: 62/736,005. Filed on 09/25/2018).

Martín-Martínez M, Pérez-Gordillo FL, Álvarez de la Rosa D, Rodríguez Y, Gerona-Navarro G, González-Muñiz R, Zhou MM. “Modulating Mineralocorticoid Receptor with Non-steroidal Antagonists. New Opportunities for the Development of Potent and Selective Ligands without Off-target side effects” (R, REV) J. Med. Chem 2017, 60(7), 2629-2650

Ming-Ming Zhou, Guillermo Gerona-Navarro, Yoel Rodriguez, Patrizia Cassaccia. “Small Molecules Transcription Modulators of Bromodomains” (R) US Patent, Number: 10065951. Filed on 05/29/2015).

Gacias, M.*; Gerona-Navarro, G.*; Plotnikov, A.N.; Guangtao, Z.; Lei, Z.; Kaur, J.; Moy, G.; Rusinova, E.; Rodriguez, Y.; Matikainen, B.; Vincek, A.; Joshua, J.; Casaccia, P. & Zhou, Ming-Ming . “Selective Chemical Modulation of Gene Transcription Favors Oligodendrocyte Lineage Progression” (R) Cell Chem. Biol. 2014, 21(7), 851-854. *These authors contributed equally to this work.

Grants over the last 5 years

Ongoing Research Support

National Institutes of Health
1SC1GM136635-01                           Gerona-Navarro (PI)                           04/01/20 – 03/31/24
“Allosteric Modulators of Polycomb Repressive 2 Gene Repression as Potential Therapeutics for the Development of Novel Epigenetic Cancer Therapies”
Amount Funded: $1,570,000
Role: PI

Research Foundation of CUNY, The City University of New York
PSC CUNY Traditional B Grant         Gerona-Navarro (PI)                   06/01/2020 – 05/31/2021 “Allosteric Modulators of Polycomb Repressive 2 Gene Repression as Potential Therapeutics for the Development of Novel Epigenetic Cancer Therapies”
Amount Funded: $6000
Role: PI

Completed Research Support

National Institutes of Health
1SC2GM111231-01                           Gerona-Navarro (PI)                  08/01/2014 – 05/31/2018
“Chemical Probes Targeting Polycomb Repressive Complex 2 Gene Repression”
Amount Funded: $471,000
Role: PI

Research Foundation of CUNY, The City University of New York
PSC CUNY Traditional B Grant         Gerona-Navarro (PI)                   06/01/2018 – 05/31/2019 “Targeting VEFS-SUZ12: An alternative Strategy to Develop Novel Epigenetic Cancer Therapies”
Amount Funded: $6000
Role: PI

National Institutes of Health
1R03NS072578-01(R03)                     Gerona-Navarro (PI)             12/01/2010 – 11/30/2012 “Small Molecules Modulating Oligodendrocyte Lineage Progression”
Amount Funded: $168,000
Role: PI

• Tel: 1.718.951.5000 ext. 3619

Academic Appointments:

Associate Professor (Sept. 2020), Chemistry Department, Brooklyn College, The City University of New York
Doctoral Faculty, Chemistry PhD Program, The Graduate Center, The City University of New York
Doctoral Faculty, Biochemistry PhD Program, The Graduate Center, The City University of New York

Degree(s)

Ph.D. Chemical Physics (1996), Columbia University, New York, NY
M.Phil. Chemical Physics (1994), Columbia University, New York, NY
M.A. Chemistry (1992), Columbia University, New York, NY 

Research Focus:

My background is in statistical thermodynamic theory and computational modeling. My laboratory is primarily involved in the development and application of  molecular computational models of protein-drug binding and macromolecular molecular recognition phenomena.  The overall aim of the research is to deploy sophisticated molecular theories, efficient algorithms, and powerful computers to characterize fundamental chemical and biological mechanisms and work with colleagues to help address human health issues.  The specific application area we are currently targeting  is the computational screening of potential drugs against protein receptors using massive atomistic computer simulations and accurate free energy models. Computer models are nowadays an important and established component of modern and interdisciplinary structure-based drug discovery programs. The advanced molecular dynamics-based binding free energy methods that we target, in particular, are attractive because they can yield estimates of binding constants useful for ranking the inhibitory potency of drug candidates and for direct comparison to binding affinity measurements. Computational studies of this kind yield valuable information about the energetic, structural, and dynamical behavior of drug-receptor complexes to complement medicinal chemistry efforts. Our research is intrinsically collaborative and interdisciplinary. As illustrated by the published works below, we regularly partner with medicinal chemistry laboratories to increase the chance of success of drug discovery programs against viral infections, cancer, and drug addiction among others.

Selected Recent Publications

1. Rajat K. Pal and Emilio Gallicchio. Perturbation Potentials to Overcome Order/Disorder Transitions in Alchemical Binding Free Energy Calculations. Chem. Phys. 151, 124116 (2019).
2. Rajat K. Pal, Steve Ramsey, Satishkumar Gadhiya, Pierpaolo Cordone, Lauren Wickstrom, Wayne W Harding, Tom Kurtzman, Emilio Gallicchio. Inclusion of Enclosed Hydration Effects in the Binding Free Energy Estimation of Dopamine D3 Receptor Complexes. PLoS ONE 14(9): e0222902 (2019).
3. Denise Kilburg and Emilio Gallicchio. Assessment of a Single Decoupling Alchemical Approach for the Calculation of the Absolute Binding Free Energies of Protein-Peptide Complexes. Frontiers Molecular Biosciences: Molecular Recognition 5, 22 (2018).
4. Baofeng Zhang, Denise Kilburg, Peter Eastman, Vijay S. Pande, Emilio Gallicchio. Efficient Gaussian Density Formulation of Volume and Surface Areas of Macromolecules on Graphical Processing Units. Comp. Chem. (2017).
5. Baofeng Zhang, Michael P. D’Erasmo, Ryan P. Murelli, Emilio Gallicchio. Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV-1 Reverse Transcriptase. ACS Omega. 1, 435-447 (2016).

Grants over the last 5 years

Emilio Gallicchio, PI
NSF CAREER
1750511
Theory, Models and Computer Simulation of Molecular Recognition Processes
9/1/2018-8/31/2023

• Tel: 1.718.951.5000 Ext. 2499
• Website: Link

Academic Appointments:

Professor, Chemistry Department, Brooklyn College, The City University of New York
Faculty, Chemistry, Biology and Biochemistry PhD Programs, The Graduate Center, The City University of New York

Degree(s)

Ph.D. (Chemistry) Public University of Navarra, Spain
M.S. (Inorganic Chemistry), University of Zaragoza, Spain

Research Focus:

My research program focuses on the synthesis and characterization of transition-metal complexes (early and late transition metals such as gold, silver, copper, platinum, palladium, ruthenium and titanium) and their applications as: a) anticancer and antimicrobial agents and b) as catalysts in reactions of industrial interest (including but not limited to oxidations and C-C and C-Heteroatom bond formation). In the cancer field, the long-term goal of my research is the development of novel metal-based chemotherapeutics for different diseases that can overcome some of the drawbacks associated with the use of existing drugs. My group has focused on the synthesis of new potential anticancer agents based on gold, platinum, palladium and ruthenium and iminophosphorane ligands endowed with promising activities displaying a mode of action different to that of the most commonly used metallodrug: cisplatin. Recently, we have unveiled the potential of a water-soluble ruthenium compound as a breast cancer chemotherapeutic which shows an impressive tumor reduction size in vivo in mice (xenograft model). We have also focused on the preparation of heterometallic gold complexes as anticancer agents. Our hypothesis is that the incorporation of two different metals with anti-tumor properties in the same molecule will improve their activity due to: a) interaction of the different metals with multiple biological targets and b) improved chemicophysical properties of the resulting heterometallic compound. In this context, we have reported that such an approach is a feasible one and that new titanium- and ruthenium-gold complexes may be promising candidates with improved antitumor properties with respect to their monometallic (titanium, ruthenium and gold) precursors in renal cancer (with impressive tumor reduction size in vitro in xenograft models in mice, displaying anti-migratory properties and, in some case anti-angiogenic properties). More recently, we are working on more targeted therapies by improving the delivery of some of these and other metal-based cytotoxic agents by: a) using enzyme-cleavable biodegradable nanocarriers, and, b) using monoclonal antibodies to generate potent antibody-drug conjugates that are specific to certain cancerous tumors.

Selected Publications

Elie B, Hubbard K, Layek B, Seok Yang W,  Prabha S, Ramos J, Contel M. (2020) Auranofin-Based Analogues Are Effective Against Clear Cell Renal Carcinoma In Vivo and Display No Significant Systemic Toxicity. ACS Pharmacol. Transl. Sci.  https://doi.org/10.1021/acsptsci.9b00107

Del Solar V, Contel M. (2019). Metal-Based Antibody Drug Conjugates. Potential and Challenges in Their Application as Targeted Therapies in Cancer. J Inorg Biochem; https://doi.org/10.1016/j.jinorgbio.2019.110780.

Elie BT, Hubbard K, Pechhenyy Y, Layek B, Prabha S, Contel M. (2019). Preclinical Evaluation of an Unconventional Ruthenium-Gold-Based Chemotherapeutic: RANCE-1, in Clear Cell Renal Cell Carcinoma. Cancer Med; 4304 https://doi.org/10.1002/cam4.2322 (open access).

Curado N, Dewaele-Le Roi G, Poty S, Lewis JS, Contel M. (2019). Trastuzumab gold-conjugates: synthetic approach and in vitro evaluation of anticancer activities in breast cancer cell lines. Chem. Commun; 55, 1394. DOI: 10.1039/c8cc08769e.

Curado, N, Contel M. Heterometallic Complexes as Anticancer Agents In: Metal-based Anticancer Agents (Series Metallobiology). (A, Casini, S. Meier-Menches, A. Vessieres Eds.), Royal Society of Chemistry. 2019. https://pubs.rsc.org/en/content/chapter/bk9781788014069-00143/978-1-78801-406-9.

Patents

Contel M, Marzo I, Frik M, Elie BT. Arene ruthenium (II) derivatives containing iminophosphorane ligands and their use in cancer therapy. US Patent 9,555,049 B2 (01/31/2017).

Contel M, Fernández-Gallardo J, Elie BT, Ramos JW. Titanocene Gold Derivatives Comprising Thiolato Ligands. US Patent 9,315,531 (04/19/2016).

Grants over the last 5 years

Contel, PI
NIH/NIGMS
2SC1GM127278-05A1
Biodegradable nanocarriers and antibodies as targeting delivery vehicles for cancer metallodrugs
06/01/18-05/31/2022

Contel, PI
NIH/NCI
1SC1CA182844
Titanium-gold-based chemotherapeutics for prostate and kidney cancer
07/01/13-05/31/2018

• Tel: 1.718.951.5000 Ext. 2833
• Website: Link