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Current Trainees 


Cao, MinhuaMinhua Cao

BA Chemistry, Hunter College of City University of New York - 2019

Program/Dates Supported by NIGMS: Chemistry/ July 2021-present

Title:  Metallophores as tools for antibiotic drug development and the study of bacterial metal homeostasis

The Microbial infection is closely tied to nutrient acquisition. Bacteria rely on iron acquisition from the host for survival, the host iron is sequestered as Fe 3+ by bacterially produced metallophores termed siderophores. While biding Fe 3+ efficiently, siderophores also present high affinity toward other metal ions such as Ga 3+, Sc 3+, and In 3+ which share similar size and coordination chemistry with high-spin Fe 3+. Previous studies have shown these Fe 3+ mimics display growth inhibitory activity.  The over-arching goal of my project is to investigate how the metallophore-mediated transport of Ga 3+, Sc 3+, and In 3+ takes advantage of the iron siderophore acquisition mechanism and identify which cytoplasmic targets are affected that result in the observed growth-inhibitory activity. To address these questions, we aim to develop metallophore probes designed to incorporate a 67Ga or 124I label for metabolic tracking and photoaffinity probes incorporating a fluorescent diaziridine photoaffinity tag, for the isolation and identification of proteins involved in active trans-membrane transport. These metallophore probes have the potential to be useful tools to uncover siderophore conjugate mechanism of action and further improve their efficacy.


Corbo, ChristopherChristopher Corbo

B.E. in Chemical & Molecular Engineering, Stony Brook University

Program/Dates Supported by NIGMS: Biochemistry and Structural Biology/ July 2021-present

Title:  Dynamic scoring for de novo design of molecules

Computer aided drug design is an integral part of modern drug discovery, particularly for hit identification. A hit is typically defined as a molecule which has a micromolar affinity for a protein target and is a starting point for optimization. This stage of drug development is particularly amenable to the use of computational techniques as they can search large areas of chemical space in a quick and efficient manner. My research aims to further improve this process via the development of new routines and algorithms in DOCK6. 

One such method for hit identification is the fragment by fragment construction of molecules within the constraints of a binding site, called de novo design. Currently DOCK6 can bias the construction of molecules towards those which are more similar to a given reference molecule, such as an experimentally validated inhibitor. This is achieved through the use of similarity-based scoring functions which assess the similarity of growing molecules to the reference molecule. Those which are most similar are advanced to subsequent stages of growth. However this inadvertently creates a bias for molecules which are bulkier at early stages of growth, and leads to ill-informed decisions. I believe that by reconstructing the reference molecule in parallel to the growth of new molecules, a higher degree of similarity can be achieved. This dynamic scoring will further focus the search for new hits in areas of chemical space which are likely to be successful, while still identifying novel chemical structures.


GilbertiAlexa Gilberti

BS in Chemistry, Stony Brook University, magna cum laude

Program/Dates Supported by NIGMS: Chemistry/ July 2020-present

Title:  Targeted protein Degradation of SMG-1

Serine/Theonine protein Kinase one (SMG-1) is involved in nonsense mediated mRNA decay (NMD) which is one of the DNA Damage Response (DRR) pathways in mammalian cells.  The DDR serves to detect, fix, or ameliorate errors that may arise during DNA replication, and if left unchecked can lead to cell cycle arrest, regularion of DNA replication, and the failure to repair of DNA damage.  DDR plays an important role in protecting cancer cells from chemotherapeutics, and the underlying hypothesis of this project is that inhibition of SMG-1 will senstive cancer cells to cancer therapies as well as the immune response.  However, efforts to evaluate this hypothesis using genetic knockouts in breast cancer cells have been hindered by the essentiality of SMG-1.

Proteolysis targeting chimeras (PROTACs) utilize the cells natural ubiquitin proteasome system for protein degradation and maintaining homeostasis in the eukaryotic cells, in order to force the initiation of a degradation cascade on a target. In order to determine if SMG-1 is a suitable target for PROTAC development, we will utilize the Achilles TAG (aTAG) tool that was developed by C4 Therapeutics to knockdown the SMG-1 protein. A fusion protein of the aTAG with SMG-1 will be created using CRISPR/Cas9, and PROTACs directed at the aTAG will be used to degrade the aTAG/SMG-1 fusion protein. Targeted protein degradation with PROTACs will be used to chemically knockdown SMG-1 and evaluate SMG-1 as a potential therapeutic target.


GilbertiYongLe He

BS in Chemistry, Stony Brook University, 2019

Program/Dates Supported by NIGMS: Chemistry/ January 2022-present

Title:  Mechanistic studies of BLUF and LOV photoreceptors and photoswitchable fluorescent protein

Photoreceptors are light-sensitive proteins that contain a chromophore responsible for sensing and responding to light in a variety of organisms. They have unique applications in the field of optogenetics where light can be used to modulate biological functions. My research involves the characterization of two groups of photoproteins: the blue-light using FAD (BLUF) and light oxygen voltage (LOV) domain photoreceptors where excitation results in structural changes that ultimately lead to biological processes such as photosynthesis, visual transduction, and circadian rhythms. For the BLUF and LOV proteins, our aim is to elucidate the signaling transduction mechanism from the chromophore binding domain to the effector domain using time-resolved infrared spectroscopy combined with chemical and structural biology techniques. Currently, we are investigating multiple BLUF (AppA, PixD, and BlsA) and LOV (AsLOV2, YtvA, and El222) proteins. Also, we are correlating the structural activity relationship of the photoactivated domain with the functionally relevant effector domains, such as PixD-PixE complex (controls phototaxis), AsLOV2-PAC1 (optogenetic construct), YtvA-FixL1 (histidine-phosphotransferase and Kinase), and El222-DNA complex (transcriptional factor).

In addition, we also study the photoswitchable fluorescent protein that can be reversibly switched between bright and dark states.  The main goal is to characterize the photoswitching mechanism in Dronpa2 using vibrational spectroscopy (IR and Raman), isotope labeling, and unnatural amino acid incorporation. Previously, we successfully used IR and Raman spectroscopy to explain the photoswitching isomerization of the Dronpa chromophore, and we want to extend our study to its homolog Dronpa2. Ultimately, this knowledge can drive the development of more optogenetic tools and the application of photoswitchable proteins in super-resolution microscopy.


Francis Boadi CBTP 2020Steven Pak

PharmD , St John’s University, 2016

Program/Dates Supported by NIGMS: Molecular and Cellular Pharmacology/ July 2020-present

Title:  Virtual screening of small molecule inhibitors for mutated fibroblast growth factor receptor 2 in intrahepatic cholangiocarcinoma

My goal of my proposed research is to discover small molecule inhibitor for mutated fibroblast growth factors 2 in intrahepatic cholangiocarcinoma patients (ICC). ICC is a deadly liver cancer that includes very few treatment options. A large group of patients that presents all types of liver malignancies present ICC. Without adequate treatment, life expectancy after diagnosis is very short. Currently, there are no specific inhibitors for the mutational active FGFR2. Therefore, the goal of this project is to design small molecular candidates through virtual screening to bind to the binding site of the mutated FGF2.

By utilizing crystallographic structures of hyperactive FGFR2, structural models were prepared for docking simulations. Because mutated FGFR2 does not exist, additional models will need to be created for simulation. Then, large-scale virtual screening of commercially available compound libraries will be used to identify potential drug-like ligands. After virtual screening, results were ranked ordered via relevant scoring functions. Then, subsets of the most promising ligands will be purchased and tested for activity.


Francis Boadi CBTP 2020Rachel White

BS in Biology, Pepperdine University

Program/Dates Supported by NIGMS: Molecular Genetics and Microbiology/ July 2020-present

Title:  The Role of Host Protein TFII-I in Adenovirus Infection

For successful viral replication to occur, viruses must be able to subvert host cell immune mechanisms. In Adenoviruses, a family of nonenveloped DNA viruses, the Adenovirus early protein E4ORF3, a SUMO E3 ligase, has been shown to inhibit host responses that could otherwise block viral replication.  Examples of targets with known functions include several involved in detecting and repairing double-strand DNA breaks, such as the Mre11-Rad50-Nbs1 (MRN) complex and p53. If not inhibited by the virus, these proteins can negatively impact Ad replication by responding to the virus’ double-stranded DNA genome as they would to a chromosomal double-strand DNA break. E4ORF3 also targets PML nuclear bodies, which are involved both in cell responses to DNA damage and in transcriptional regulation and antiviral responses such as the interferon response.  Another major target of E4ORF3 is the transcription factor TFII-I, which suggests that it is involved in suppressing Ad infection. TFII-I is involved with multiple transcription pathways, including some activated by p53 in response to DNA damage, and can inhibit the transcription of the Ad protein L4, which is important for the transition between early and late viral transcription in Ad infection.  Some studies have also associated TFII-I with the DNA Damage Response that the MRN complex functions in. However, its exact function in Ad infection is not known, and represents an important area of research to better understand the cellular mechanisms involved in Ad infection and possible general functions of TFII-I in viral infections. 

Our lab has already created TFII-I CRISPR knockouts in normal human bronchial epithelial cells (NHBEC), and Ad strains that lack E4ORF3. I am also currently developing TFII-I CRISPR knockouts in small airway epithelial cells (SAEC). The goal of my project is to investigate cellular antiviral responses to Ad infection and Ad expression of early and late viral proteins both with and without TFII-I and E4ORF3 expression.  Such investigation has the potential to increase our understanding of TFII-I as an anti-viral effector protein and of cellular mechanisms with the potential to block DNA viruses from successfully completing infection.


WithornJason M. Withorn

BS Biochemistry and Chemical Biology from Wayne State University in Biology, Pepperdine University

Program/Dates Supported by NIGMS: Chemistry/ July 2021-present

Title:  Functional characterization of the NosP associated histidine kinase, NahK, and its role in biofilm formation in Pseudomonas aeruginosa

Biofilms are multicellular communities formed when bacteria attach to a surface and secrete a thick, mucoid protective barrier known as the exopolysaccharide matrix (EPS). The EPS is composed of polysaccharides, extracellular DNA, and proteins. The EPS encompasses the cell promoting a nutrient rich environment that prevents antibiotics from reaching the cell.

It has been shown that the diatomic gas, nitric oxide (NO), facilitates the dispersal of biofilm-forming bacteria, reverting to a planktonic state. In 2017, our group discovered a novel heme-binding protein named NosP, nitric oxide sensing protein which functions to inhibit the NosP associated histidine kinase, NahK, which is located on the same operon. Our group has shown that when these two proteins are deleted, the bacteria are unable to form complex biofilm structures and they lose the ability to respond to toxic levels of NO. My project focuses on the pathogen Pseudomonas aeruginosa, which has been identified as a priority one pathogen needed a new treatment according to the World Health Organization. My project focuses on elucidating the function of NahK in vivo, and determining the role of the three uncharacterized PAS sensory domains located on the kinase.  Understanding how NahK’s function in regards to signaling changes could allow for a more in depth understanding of NO-mediated biofilm dispersal, and allow for a more efficient treatment of biofilms to be developed.


Francis Boadi CBTP 2020Francis Boadi 

BA in Chemistry, Rutgers University

Program/Dates Supported by NIGMS: Chemistry/ 2019-2021

Title:  Developing pH-sensitive copolymers and glycopolymers with sequence-defined backbone

A significant number of pH sensitive polymers are biodegradable. For this matter, they have the potential to play relevant roles in life. Biodegradable polymers/plastics have been championed in the last four decades owing to a myriad of opportunities they present including environmentally friendly and biocompatibility. Generally, there are two classes of biodegradable polymers which are natural and synthetic. Synthetic polymers offer more advantages than natural polymers because synthetic tool offers handles to modify and functionalize polymers to suit certain applications. To an extent, with synthetic tools, we can bridge the gap between natural and synthetic polymers. Notable synthetic biodegradable polymers are poly-L-lactic acid (PLLA), polyglycolic acid (PGA)/polylactic acid (PLA), polycaprolactone (PCL). These polymers are mostly synthesized by condensation techniques which makes it somewhat impractical to prepare polymers with incredibly high mechanical strength. For this reason, we sought to develop methodology which would enable us to prepare very long high molecular weight polymers which are readily degradable. Our group has developed a type of polymerization called alternating ring opening metathesis polymerization (AROMP). Together with my colleague, Jingling Zhang, we have successfully prepared high molecular weight polymers using AROMP. What is interesting is that these polymers have ester and acetal functionalities in their backbone which are readily degradable under basic and acid conditions respectively. This would possibly have applications in drug delivery and lithographic patterning.

Synthetic tools provide handles to have access to natural polymers. Multivalent sugars have shown to have better efficacy compared to monovalent sugars. Using polymerization method such as ring opening metathesis polymerization (ROMP) and norbornene as the backbone scaffold. Our group has developed several sugar polymers. These glycopolymers, mannose, fucose, GlcNAc, have shown to induce acrosomal exocytosis of male sperm. Galactose and fucose polymers have also shown to bind to cholera toxins. The mechanism of action in these cell binding processes are not well understood. The glycopolymers used in these studies are based on polynorbornene scaffold which tend to lack sequence-definition. Nature’s heavy reliance on sequence have caused us to reason that having sequence-control in our glycopolymers’ backbone would enhance their efficacies. Therefore, my goal is to use AROMP to prepared and sequence sequence-defined copolymers of sugars.


John Bickel

Francis Boadi CBTP 2020 BS in Chemistry, Truman State University

Program/Dates Supported by NIGMS: Chemistry/ 2020-2021

Title:   Strategies for biasing de novo design in DOCK6

The goal of my proposed research is to further develop and improve the from-scratch construction algorithm (de novo design) as currently implemented in DOCK6 for the purposes of constructing potential compounds designed for a specific target. As libraries of compounds on public databases such as ZINC15 continue to grow in size at an astounding rate (currently ~750M), performing a full virtual screen of these libraries against potential drug targets is becoming increasingly infeasible given the current docking architecture. By constructing these compounds directly to the site of interest, there is a higher probability of the resulting compounds to have higher specificity and tighter binding interactions.

The ultimate goal in improving and optimizing the DOCK6 de novo algorithm is to be able to effectively bias construction of new molecules such that populations of newly constructed torsion types (allowable bond types) more closely match the distribution of torsions of an input library derived from drug-like compounds. This goal is being addressed by implementation of a fitness proportionate (roulette) method of selection, as well as implementation of new ways of handling DOCK6’s database of fragments and their associated bonding pairs.


Francis Boadi CBTP 2020Jiayuan Fu

BS, Beijing Normal University, 2018

Program/Dates Supported by NIGMS: Chemistry/ 2019-2021

Title:  Characterization of a Novel Nitric Oxide/Heme Sensing Protein and its Role in
Regulating Biofilm Formation in Burkholderia Thailandensis

Bacteria use two-component system to sense and respond to environmental cues. Two component systems usually are composed of sensory histidine kinase and response regulator, the effecter domain of the latter is tightly regulated by its phosphorylation state. Two-component systems modulate bacterial physiological processes including motility, biofilm formation and virulence factor secretion. Particularly, a lot of these processes are indirectly controlled by two-component system via the production or degradation of secondary messengers, one of the examples is cyclic-di-GMP, high level of which contribute to robust biofilm formation in most bacteria species. As biofilms are surface attached microorganisms that are shielded within extracellular polymeric substances, they cause a lot of antibiotic resistance. People are getting interested in using small molecules to trigger the dispersal of biofilms, one of the most promising one is nitric oxide.

We identified a two-component system and its co-cistronic sensor protein NosP from Burkholderia thailandensis, the close surrogate of highly infectious Burkholderia pseudomallei which cause serious tropical disease melioidosis. We proved successful kinase autophosphorylation and phosphoryl transfer from the kinase to the receiver domain of response regulator. By site-directed mutagenesis, we were also able to identify the key residues that contribute to the phosphorelay, which are a histidine from the kinase and an aspartate from the response regulator. The cognate sensor protein of this two-component system, which termed as NosP, is a heme-based sensor which possibly conduct signaling transduction to the kinase via protein-protein interaction. NosP uses label heme as signaling molecule, as heme-bound NosP inhibit kinase autophosphorylation while apo-NosP does not. NosP displayed very fast heme dissociation rate, much faster than that of obligated heme proteins such as sGC and myoglobin. NosP also displayed very fast nitric oxide dissociation rate, comparable to that of well characterized NO sensor that could detect nano to picomolar nitric oxide.

In the future, we would like to know whether NO-ligated NosP will modulate kinase activity. We will also test the activity of the effector domain of the response regulator, as sequence analysis indicate a conserved phosphodiesterase motif within the effector domain that could possibly degrade c-di-GMP. We would also like to know how phosphorylation regulate the effector domain activity. Finally, we would like to know how NosP-based NO/Heme signaling regulate biofilms.


GunawhardhanaNipuni Gunawardhana

BS in Chemistry, University of Colombo, Sri Lanka

Program/Dates Supported by NIGMS: Chemistry/ 2020-2021

Title:  Astrocyte Specific Delivery of Methyl-Pyridinium Tagged Small-Molecule Cargo

Neurons were the big players in neuroscience research until recent efforts identified that astrocytes too are active players in brain function. Astrocytes are the most abundant type of non-neuronal cells in the brain. In addition to maintaining blood-brain barrier integrity and providing nutrients to the surrounding cells, astrocytes form a specialized structure with pre- and post-synaptic neurons known as the tripartite synapse where they take part in the uptake and release of neurotransmitters. Astrocytes have been implicated in many neurological diseases  like Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), glioblastoma and depression. Accordingly, to understand how the brain circuitry functions it is essential to study astrocytes.

However, only a limited number of strategies are available for astrocyte visualization and manipulation. These existing methods lack specificity and versatility. A new class of methyl-pyridinium tagged fluorescent markers has been developed in our lab that shows specific targeting and visualization of astrocytes. The positive charge of the methyl-pyridinium targeting moiety of this probe allows active transport of diverse cargo such as Ca 2+ sensors, small molecule drugs and transcriptional activators to astrocytes through the astrocyte resident Organic Cation Transporter (OCT).

I am currently synthesizing a methyl-pyridinium tagged cyanodoxycycline to activate transcription of specific genes in astrocytes using the tetracycline-inducible gene expression (Tet-On) system. My work is also focused on the drug tamoxifen to create a traceless astrocyte delivery strategy. These molecules will help us to evaluate the ability of the targeting moiety to deliver drugs specifically to astrocytes. This strategy will be beneficial for exploring the therapeutic aspects of astrocytes in various neurological diseases and will improve our understanding of the functions of astrocytes in the brain.


Kirsten Martin CBTP 2020Kirsten Martin

BS  in Chemistry

Program/Dates Supported by NIGMS:  Chemistry  / 2019-2021

Title:   I n Situ Excitation of Luminescent Lanthanide Complexes: Towards Enabling In Vivo Bioimaging

Optical imaging probes are indispensable tools for the visualization of biomarkers of disease without perturbing the biological system. Ideal optical imaging probes provide low limits of detection, minimal photobleaching and emit in the first or second biological window (550-800 nm and 1000-1350 nm). Luminescent lanthanides exhibit many of these aforementioned properties, however, as f-f transitions are Laporte-forbidden, organic chromophores absorbing in the 200-300 nm range, known as antennae, are necessary for efficient excitation of the metal ion. These excitation wavelengths are not compatible with biological applications due to the strong absorbance of proteins and hemoglobin at wavelengths below 550 nm. To circumvent this, we proposed that lanthanide-based complexes could be excited in situ using Cherenkov radiation. Cherenkov radiation is generated by charged particles emitted during the decay of radioisotopes in dielectric media in the form of the emission of short wavelength light with a maximum below 400 nm. In situ excitation of lanthanide complexes with Cherenkov radiation energy transfer (CRET) eliminates the need for external high energy, short wavelength excitation.

Following our initial proof of concept, we have demonstrated that CRET is suitable to excite discrete Tb and Eu complexes with a detection limit of 5 nmol and 10 nmol, respectively. We have demonstrated efforts towards the application of these complexes for multiplexed imaging and the targeted in vitro and in vivo imaging of prostate cancer by targeting the prostate-specific membrane antigen (PSMA). The targeted and nontargeted europium and terbium-based probes produce moderate quantum yields (10-47%) and are efficiently excited with Cherenkov radiation with radioisotopes 18F and 89Zr.  The lanthanide-based emission was monitored and quantified using a small animal fluorescence imager. With only 10 μCi of 18F, quantities as low as 10 nmol of Eu and as low as 5 nmol Tb complex can be detected. These LOD’s compare favorably with optical chromophores requiring external excitation. Stability assessments and cell binding assays of the complexes are ongoing.


Luz photoLuz Mendez 

BA with honors, Wesleyan University, 2017

Program/Dates Supported by NIGMS: Chemistry/ 2018-2021

Title:    Identifying Inducers of the Acrosome Reaction in Human Sperm with Synthetic Glycopolymers

  The acrosome reaction (AR) in spermatozoa is an essential process in mammalian fertilization. Although the mechanism behind the activation of AR is not well-understood, it is known that the glycoproteins surrounding the egg cell’s zona pellucida (ZP) can mediate the activation of AR through a series of carbohydrate binding events with the receptors on the sperm plasma membrane. Previous research in the Sampson lab has demonstrated that AR in mouse sperm can be induced successfully in vitro with the aid of glycopolymers. These glycopolymers, synthesized by ring-opening metathesis polymerization (ROMP), possess norbornene backbones and resemble terminal residues of the sugar moieties present on the ZP. These glycopolymers are hypothesized to be potential inducers of AR in human sperm. To determine the efficacy of AR induction by glycopolymers, a flow cytometry assay is currently under development, which will allow for efficient sorting and quantitative analysis of dead, live, and acrosome-reacted cells. With the aid of this assay, promising AR inducers can be identified and will allow for the distinction of sperm that are able to participate in fertilization and those that are not. The development of this flow cytometry assay will ultimately provide the clinical community with a new method of assessing male infertility that can predict AR activation, thus improving current techniques used for diagnosis and treatment.

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ParkinLia Parkin

B.A., cum lade , Cell & Molecular Biology, Barnard College, Columbia University, 2018

Program/Dates Supported by NIGMS: Molecular Genetics and Microbiology / 2020-2021

Title: Towards understanding the lipid transport pathway LprG-Rv1410c in mycobacteria, and its contribution to outer membrane biogenesis, membrane permeability, and antibiotic susceptibility

Mycobacteria, including the human pathogen Mycobacterium tuberculosis (Mtb) that causes tuberculosis (TB) , have a complex and impervious double membrane that distinguishes them from Gram negative and Gram positive bacteria. Unfortunately, Mtb infects one fourth of the global population. More disturbingly, new cases of Mtb are increasingly resistant to frontline therapies. By elucidating mycobacterial membrane biogenesis pathways, we can reveal new drug targets and identify proteins that control membrane permeability.

The Jessica Seeliger lab focuses on the LprG & Rv1410c proteins, which form an operon and likely work together to transport lipids to the outer membrane of mycobacteria, more specifically referred to as the mycomembrane. Loss of the LprG-Rv1410c operon leads to attenuation in vivo and a growth defect under nutrient limitation in vitro. We recently used a computational docking screen in search of commercially available small molecule inhibitors of LprG. We discovered molecules that inhibit mycobacterial growth in an LprG-dependent manner with micromolar affinity, indicating that LprG can be specifically inhibited. Additionally, we found that a single residue in the cavity of LprG mediated interaction with one of our most potent compounds. Overall, despite having a large and generally hydrophobic pocket, LprG can be realistically inhibited and rational drug design is feasible.

Understanding LprG-Rv1410c mediated lipid transport is also of interest because these proteins are predicted to be important for intrinsic resistance to multiple TB antibiotics. It has also been shown experimentally that the loss of the LprG-Rv1410c operon leads to increased susceptibility to certain antibiotics. Therefore, targeting or inhibiting LprG-Rv1410c may promote the efficacy of antibiotics that normally cannot cross the mycomembrane efficiently.

In future studies, we will determine how LprG & Rv1410c mechanistically mediate lipid transport, in order to obtain a model of mycobacterial lipid transport to the mycomembrane. Additionally, we will investigate how LprG & Rv1410c affect membrane permeability in order to better understand drug diffusion across the mycomembrane. Ultimately, this work will better define mechanisms of mycobacterial membrane biogenesis and drug uptake. 


Danielle pic

Danielle Cervasio

B S,  s umma cum laude ,   SUNY Cortland, 2017

Program/Dates Supported by NIGMS: Chemistry/ 2018-2021

Title:  Translational applications of small-molecule, astrocyte-targeted probes

Astrocytes are the most abundant non-neuronal cell type in the brain, providing support, nutrient buffering, and instructions to neighboring cells, particularly neurons, in order to maintain normal physiological function and homeostasis. Importantly, astrocytes play a large role in the brain by responding to insult, communicating with neurons via gliotransmitters, and forming protective barriers around endothelial cell layers. Because astrocytes are present abundantly in all cortical areas of the brain, performing essential metabolic, structural, and homeostatic roles, it is not surprising that they are implicated in a slew of disease and disorders, including, but not limited to, Alzheimer’s, Parkinson’s, glioblastoma, stroke, seizure, infection, and depression. Thus, it is becoming increasingly important to consider these cells for therapeutic intervention of such disease, seeing that they are important players in maintaining normal brain function. In leveraging organic cation transporters (OCTs) on the surface of astrocytes, we have developed a system by which a permanently positive N-heterocyclic amine can be attached, via organic chemistry, to diverse small molecules like fluorophores, photoactivatable markers, or calcium indicators and delivered specifically to astrocytes over neurons and other glia (Fig. 1a and b). These data have inspired us to think about more translational applications, including the potential to deliver drugs or transcription activators to astrocytes for therapeutic intervention. Gene-targeted therapies are currently in the clinic, but there exists a lack of regulated systems. We currently have some control over where, but no control over when therapeutic genes are expressed. I plan to synthesize and assay a doxycycline modified with a permanently positive N-heterocycle to exploit the powerful tetracycline-inducible gene expression system (Tet-On/Off) in order to control gene expression in astrocytes, exclusively. In adding this modification, I hypothesize that we will be able to target astrocytes for therapeutic intervention, decrease concentrations of drug needed by increasing blood brain barrier (BBB) penetration, and reduce off target effects of current constitutively active therapies as seen in Glial cell-derived neurotrophic factor (GDNF) or Neurturin (NTN) gene therapy for Parksinson’s disease.  
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  Stephen Collins

Program/Dates supported on the NIGMS Grant:  Biochemistry and Structural Biology/2016-2017

Title: Inhibitor Development for Cancer-Associated Mutants of Human Epidermal Growth Factor Receptor 2 (HER2)

A subset of human epidermal growth factor receptor 2 (HER2) mutations uncovered by breast cancer genome sequencing and confirmed by the Miller lab cause deregulated kinase activity and signaling. These mutations likely represent driver mutations in breast cancer. By working with Jiaye Gou and Robert Rizzo a model of the active form of HER2 has been developed based on crystallographic information of epidermal growth factor receptor (EGFR) a HER2 family member with significant sequence homology. This had to be done because there is no structural information available for the active form of the kinase. Using this model and the zinc database we have been able to purchase a set of 149 compounds which represent our best chance at inhibiting HER2. By utilizing inhibitors as a chemical tools we aim to gain a more complete understanding of active HER2 which is poorly understood compared to EGFR.

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Lauren Prentis
Lauren pic

Program/Dates Supported on the NIGMS Grant: Chemistry/ 2016-2018

Title: Computational De Novo design of small molecule inhibitors for viral fusion proteins in Ebola and HIV

The goal of my proposed research is to develop and apply improved atomic level computational modeling tools to clinically relevant drug targets. The research integrates chemistry, biology, and physics-based approaches and is directly relevant to the field of Chemical Biology. My initial efforts have focused on targeting the Ebola virus (EBOV), which infects its host through fusion with the host cell membrane after endocytosis and is fatal. The glycoprotein on the EBOV surface inserts into the host membrane and as the pH drops to an acidic environment, the glycoprotein subunit 2 (GP2) changes its conformation from a mostly disordered to a stable 6 helix bundle. This structural change is thought to overcome the energetic barrier associated with lipid mixing that allows membrane and ultimately viral en try. The aim of this work is to design a small molecule candidate to bind to an outer pocket on GP2 delaying the formation of the 6 helix bundle, allowing the EBOV to be lysed by the cell. The project involves design, optimization, and use of a genetic algorithm approach that employs de novo design principles to breed small molecules for compatibility with a protein binding site. Through the use of the genetic algorithm approach, the offspring molecules will be selected as parents for following generations with different selection methods that employ the use of different scoring functions to rank an d select the ensemble. The goal is to create a novel population of molecules with enhanced binding potential compared to an initial ensemble. Importantly, the genetic algorithm approach can be used across various drug targets and although my initial efforts have focused on EBOV, I plan to apply the method to other drug discovery projects in the lab targeting HIV gp41 and fatty acid binding protein (FABP). We anticipate the use of a genetic algorithm approach in combination with our current virtual screening approach that employs docking, will be a more effective way to identify new drug leads for important drug targets.



Matthew Cifone


Program/Dates Supported on the NIGMS Grant: Chemistry/ 2016-2018

Title: Design and Synthesis of Bivalent Inhibitors Against Acetyl-CoA Carboxylase.

A major issue currently facing the pharmaceutical industry is the rise in bacterial strains that are resistant to commercially available antibiotics. There is thus an urgent need to identify new drug targets. My research project is focused on the enzyme complex acetyl-­CoA carboxylase (ACC), which participates in the first committed step of fatty acid biosynthesis and is composed of two enzymes, biotin carboxylase (BC) and carboxyltransferase (CT), as well as biotin carboxyl carrier protein (BCCP). This complex is particularly attractive because ACC is encoded differently between prokaryotes and eukaryotes, allowing us to selectively inhibit bacterial ACC. Selective and potent inhibitors of both the BC and CT domains have already been developed including the pyridopyrimidines that target the BC domain and moiramide B which inhibits the CT domain. The goal of my project is to develop bivalent inhibitors of ACC by linking the BC and CT pharmacophores using a PEG linker. The bivalent inhibitors are excepted to have higher affinity for the enzyme than either pharmacophore alone, and are also anticipated to have long residence time on the enzyme. As such, the bivalent inhibitors will be valuable tool compounds for exploring the relationship between time-­dependent enzyme inhibition and prolonged drug activity at low concentration. In addition, the bivalent compounds are also expected to have improved resistance profile than either ACC inhibitor alone. Finally, since no structure exists for the complete bacterial ACC complex, we hope that the bivalent inhibitors will stabilize the complex sufficiently to facilitate protein crystallography. Because there is no structure of the complete complex, and initial aim of my project is to experiment with linkers of different sizes to determine the optimum separation of the two pharmacophores to bridge the BC and CT domains.



  The CBTP at SBU is made possible by a generous grant from the

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