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CBTP in the news:

AAAS/CASE Workshop in DC features two CBTP fellows



Current Trainees 


Luz photoLuz Mendez 

BA with honors, Wesleyan University, 2017

Program/Dates Supported by NIGMS: Chemistry/ July 2018-present

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 same glycopolymers are hypothesized to be potential inducers of AR in human sperm. To determine the efficacy of AR induction by glycopolymers, a triple stain flow cytometry assay will be employed, allowing 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, providing 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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Danielle Cervasio

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

Program/Dates Supported by NIGMS: Chemistry/ July 2018-present

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

Non-neuronal cells of the brain, or glia, are quickly proving to be important players for modulating neural circuitry. Glial cells support, maintain, and influence neural function. Astrocytes, in particular, are glia that play a crucial role in regulating structure, formation, metabolic needs, and repair of neuronal synapses in the brain. Astrocytes are implicated in many neurodegenerative diseases including, but not limited to, Huntington’s disease (HD), Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS). Within the last few decades, emerging evidence has illuminated astrocytes as major players in brain development and maintenance, highlighting the need to visualize and target these cells and their activity. There are currently few methods to visualize astrocytes, and these methods do not offer much specificity or versatility. Using a novel small molecule targeting moiety, our lab has successfully targeted astrocytes,  in vitro and  in vivo,  by delivery of small-molecule fluorophores like Rhodamine B, and Cyanine (Fig 1a,b) .  My project is focused on expanding the repertoire of this system by introducing a variety of small molecules with varying functions. By leveraging organic chemistry, I will synthesize various small molecules substituted with our astrocyte-probe, including photo-activatable fluorophores, calcium markers, and synthetic drugs, which are of particular interest and may have implications where spatio-temporal activation or targeted drug delivery is required. Utilizing this new tool, I seek to better understand delivery of our probe as well as study how astrocytes might physically communicate and interact with neural circuits .  
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  Michael Li Mike Li photo

 BS,  s umma cum laude ,  Washington University, 2014 

 Program/Dates Supported by NIGMS: Molecular and Cellular Pharmacology MD/PhD Candidate/ May 2018-present

 Title:  Compartment-Specific Protein Labeling in Mycobacterium tuberculosis

The cell envelope of Mycobacterium tuberculosis ( Mtb) is critical to the bacterium’s survival and the target of multiple front-line antibiotics. A defining feature of the Mtb cell envelope is the periplasm, which is an enclosed compartment between the inner and outer membranes. Despite the indisputable importance of the Mtb cell envelope, the periplasm remains poorly characterized. Identifying proteins that localize and function in the periplasm is necessary to understand periplasmic biology, but this knowledge is not currently experimentally accessible. Thus, we have adapted peroxidase-mediated protein labeling to tag proteins in specific compartments within live Mtb. The method uses an engineered peroxidase, APEX2, which converts exogenously supplied labeling substrates into phenoxyl radicals that then covalently modify nearby proteins for subsequent enrichment and identification. In our application of peroxidase-based labeling to mycobacteria we have shown that we can accurately localize cytoplasmic and periplasmic proteins. We are now applying the methodology to answering key questions in Mtb cell envelope biology regarding virulence factor secretion, cell wall synthesis and lipid transport. 

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Tyler Lewis


BS, with honors, magna cum laude, Long Island University, 2015

MS, Stony Brook University, 2016

Program/Dates Supported: Molecular and Cellular Pharmacology/July 2018-present

Title:   Understanding the effects of Histone Modifications on Chromatin Structure and Dynamics

In eukaryotes, genomic DNA is organized into a DNA-protein complex called chromatin,
with the nucleosome as the repeating unit. The nucleosome is composed of a histone protein
core (an octamer containing histones H2A, H2B, H3, and H4) wrapped by 147 base-pairs of DNA. Repeating nucleosome units connected via varying lengths of linker DNA are referred to as 10- nm fiber. Nucleosomes can contact each other, forming the next level of compaction, referred to  as 30-nm chromatin fiber. Chromatin is a highly dynamic entity and its hierarchical organization  is under tight control through various epigenetic mechanisms, with histones serving as a site of  regulation via post-translational modifications (PTM). My project focuses on two functionally  antagonizing histone modifications: histone H3 Lysine 9 acetylation (H3K9Ac) and tri-methylation  on the same Lysine (H3K9me3). H3K9Ac is generally associated with transcriptional activation,  while H3K9me3 associated with transcriptional repression. Both modifications have been shown  to directly impact chromatin dynamics. The goal of my thesis project is to understand the  mechanism underlying the functional differences of these modifications. We hypothesize that  H3K9Ac and H3K9me3 modifications have distinct effects on higher-order compaction of  chromatin. I have successfully generated unmodified, canonical chromatin fiber in vitro, and I am  currently using cysteine modification strategies to install methyl-lysine or acetyl-lysine analogs in  chromatin fiber. I will use single-particle cryo-electron microscopy (EM) and in vitro biochemical  assays to obtain high-resolution structures of the different chromatin fibers. Knowledge gained  through this study will help us understand how histone PTMs perturb chromatin structure and
function by themselves and through interactions with various chromatin modifying enzymes.


Brett Vaughn

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BS, Kansas State University, 2017

Program/Dates Supported: Chemistry/ July 2018-present

Title:   Radiometal-based small molecule tracers for prostate cancer

Prostate cancer (PCa) is the second most common type of cancer diagnosed in men worldwide. Prostate specific membrane antigen (PSMA) is a transmembrane protein that is highly expressed in PCa tumors and provides a reliable target for PCa imaging. Positron emission tomography (PET) with tracers targeting PSMA has proven to be a promising avenue for non-invasive and reliable imaging of disease. Effective small molecule PSMA targeting ligands have been previously developed but exhibit non-ideal characteristics for theranostic applications. The availability of scandium and copper imaging and therapy isotopes ( 44/47Sc, 64/67Cu) enables an “apples-to-apples” comparison of imaging and therapy modality. This renders copper and scandium an attractive avenue for theranostic approaches to prostate cancer imaging. To this end, we have designed novel PSMA-conjugated scandium and copper chelators for in vivo use. My research involves the synthesis and radiolabeling of novel bifunctional chelators with systematic structural variations and PSMA targeting ability. We have synthesized and radiolabeled PSMA-targeting small molecules and used them to carry out PET imaging and biodistribution in mice bearing PSMA positive and negative tumor xenografts. Future work consists of treatment studies with therapeutic isotopes and optimization of targeting.


Jinwoo Kim

Picture of Jinwoo Kim

Program/Dates Supported: Chemistry/ September 2017-present

Title: Total synthesis of (-)-incarvillateine and development of tumor-targeted drug delivery system

Amino acid is attached to acid-liable cleavable linker-embedded anti-cancer drug conjugate as a tumor targeting module (TTM). Cancer cells are known to overexpress specific amino acid transporters because of their high demand on nutrients for their rapid growth. Specific amino acid can guide anti-cancer agent toward cancer cells because it can be recognized as its transporter substrate. Once this drug conjugate is internalized via transporter-mediated endocytosis, low pH in tumor cells enables linker to get dissociated and release anti-cancer drug out inside tumor cells. Besides this research on drug conjugate, total synthesis of (-)-incarvillateine will be undertaken to elucidate mechanism of action for anti-inflammatory agents.



Jonathan Merino


Program/ Dates Supported on the NIGMS Grant: Chemistry/June 2017-present

Title:  Synthesis of Substituted Benzoxaboroles to Target Bacterial DNA Ligase LigA via Substrate Assisted Tethered Inhibition

Benzoxaboroles are a class of drug-like molecules whose privileged scaffold has been exploited due to their excellent sugar-binding properties as well as improved water solubility, in contrast to the related phenylboronic acids. Tavaborole is an oxaborole used clinically to treat onychomycosis. The mechanism of action of tavaborole involves the formation of a covalent intermediate with leucyl-tRNA synthetase (LeuRS), an enzyme involved in protein synthesis.  X-ray crystal structures of tavaborole bound to LeuRS demonstrate that the acidic oxaborole moiety forms an adduct with the cis-diol of the adenosine ribose of tRNA Leu bound to LeuRS, trapping the substrate on the enzyme.  The Tonge group posits that the specificity of the oxaboroles can be tailored so that they form adducts with the substrate diols in the enzyme-substrate complexes of other drug targets.  This Substrate-Assisted Tethered Inhibition (SATI) approach is currently being employed to develop inhibitors of the NAD-dependent DNA ligase LigA, a target for the development of novel antibacterial agents. LigA is a promising target because the enzyme relies on NAD + as its substrate as opposed to ATP in the human homolog (Lig1). Reaction of NAD with LigA leads to a covalent enzyme-AMP intermediate, and the goal of this project is to synthesize oxaboroles that form an adduct with the AMP diol in the LigA-AMP complex.  Thus my research is focused on the development of methods to synthesize functionalized oxaboroles and to identify compounds that bind uncompetitively to LigA through the SATI mechanism LigA is a target in both Gram-positive and Gram-negative bacteria, and the long term goal of the project is to develop novel antibacterial agents that are active against drug-resistant nosocomial microorganisms.


Forrest Bowling

Picture of Forrest Bowling

Program/Dates Supported on the NIGMS Grant: Biochemistry and Structural Biology (BSB) July 2017-present

Title: Regulation and Activation of Human Phospholipase D1

Phospholipase D1 (PLD1) generates phosphatidic acid and choline through the cleavage of phosphatidylcholine. PLD1 is involved in trafficking, endocytosis, and regulation of cell metabolism. PLD1 has an elevated activity level in transformed tumor cells and has been identified as a therapeutic target for cancer. Potent and specific small molecule inhibitors have been developed and pharmacological inhibition is effective in preventing cancer cell invasion in cell culture and neoangiogenesis in mice. Biochemically, PLD1 has low basal activity and requires activation by the anionic lipid PI(4,5)P2 through an interaction within the catalytic region. The focus of my research will be to visualize the mechanism of activation and inhibition of human PLD1 by lipids and small molecule inhibitors. My preliminary data has identified two baculovirus constructs of PLD1 that when expressed in Sf9 cells are soluble and ideal for structural studies. Utilizing structural information and biochemical assays, the mechanism of activation of human PLD1 will be determined. In addition, this structural information will be used to aid design of new inhibitors with increased half-lives as tool compounds for dissecting the benefits PLD inhibition in preventing cancer metastasis.


Ilana Heckler

Ilana pic

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

Title: Nitric Oxide Mediated Bacterial Biofilm Dispersal:   Investigation of a Nitric Oxide Sensing Phosphodiesterase from Vibrio cholerae

Bacterial biofilms are non-motile communities of bacteria. They are up to 1000-fold more resistant to antibiotics than free-swimming planktonic cells. Nitric oxide (NO) is small diatomic gas capable of diffusing through the protective matrix of biofilms, and has been shown to cause biofilm dispersal at nanomolar concentrations. The Boon lab has discovered a putative, novel NO sensing domain (NosP) that coordinates NO at a heme cofactor. This domain, like other sensor domains, is often encoded with catalytic domains. NosP is thought to interact with the catalytic domains responsible for the breakdown and synthesis of cyclic diguanylate monophosphate (c-di-GMP), the secondary messenger involved in bacterial motility, virulence and biofilm. The intracellular concentration of c-di-GMP is controlled by two enzymatic activities. Diguanaylate cyclase (DGC) activity is responsible for the synthesis of c-di-GMP through cyclization of two GTP molecules, and is catalyzed by a GGDEF motif. The breakdown of c-di-GMP into either pGpG or two molecules of GMP, by a phosphodiesterase (PDE), is catalyzed by an EAL or HD-GYP motif, respectively. The goal of this work is to elucidate the role that NO plays in controlling the intracellular concentration of c-di-GMP and therefore, motility, biofilm and virulence in   Vibrio cholerae, the Gram-negative bacterium that is the causative agent of the intestinal infection cholera.   V. cholerae   encodes 22 phosphodiesterases, one of which is fused to a NosP domain. We propose that NO, upon binding to NosP, will regulate the transcription of genes involved in biofilm and virulence though activation of the hydrolytic activity of the PDE.

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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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  Eric Roth

Eric pic

Program/Dates Supported on the NIGMS Grant: Molecular and Cellular Pharmacology/2016-2018

Title: Roles of Phospholipase D1 and D2 in PyMT driven Breast Cancer Metastasis

The goal of my research is to elucidate the effects of phospholipase D (PLD) in breast cancer metastasis and metabolism to utilize and develop compounds that target metastasis. PLD is expressed in two predominant isoforms, PLD1 and PLD2, both of which generate the lipid signaling molecule phosphatidic acid through the hydrolysis of phosphatidylcholine. Both PLD1 and PLD2 have been shown to promote several early metastatic steps including migration and invasion from the primary tumor, neoangiogenesis, and survival in circulation. Although highly related, their cellular roles are not always redundant or additive, but can also be contradictory. As such, it is necessary to elucidate their separate and combined effects. In order to investigate the effects of dual inhibition, I am using the PLD1/2 inhibitor FIPI and mice genetically ablated of PLD1/2 producing a double knockout (DKO). The C57/B6 mice develop tumors from the polyoma middle-T antigen (PyMT) under expression of the mouse mammary tumor virus (MMTV). These MMTV-PyMT mice spontaneously develop multifocal mammary adenocarcinomas that regularly metastasize to the lung and lymph nodes. Previous studies have shown that PLD1 -/-  mice exhibit reduced metastasis relative to wild-type mice. My preliminary data shows a further reduction in DKO mice that results in a dramatic suppression of lung metastasis. Furthermore, DKO mice have decreased tumor burden compared to both wild-type and PLD1 -/- mice. In addition to suppressing metastasis, inhibition of PLD1 has also been shown to disrupt neoangiogenesis, autophagy, and lipid droplet formation. Collectively, this results in limited metabolic flexibility and energy reserves of tumor cells while also exposing them to hypoxic conditions. I expect these cells develop focused metabolic dependencies not present in normal cells, providing an opportunity for combined inhibition to produce synthetic lethality.


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.



James Iuliano James

Program/Dates supported on the NIGMS Grant: Chemistry/2015-2017

Title:   Ultrafast Kinetics and S tructural  Dynamics of   Light, Oxygen, Voltage Domain Proteins.

Activated proteins provide a means of high spatial and temporal control needed for the emerging field of optogenetics, in which light is used to control biological function. The most common application of optogenetics is for activating and deactivating neurons but has recently been extended to control of enzyme activity and cell signaling. Protein fusions containing light, oxygen, voltage (LOV) domains have been used as optogenetic tools, although much remains to be resolved on the mechanism of signal transduction from the flavin mononucleotide chromophore of the LOV domain to the effector domain, which can bind ligands or have enzymatic activity. The LOV proteins YtvA from Bacillus subtilis and EL222 from Erythrobacter litoralis are directly fused to effector domains through an alpha helix linker, providing model systems for studying initial light activation from the ultrafast (femtosecond) to millisecond timescales. We employ the use of ultrafast infrared spectroscopy and X-ray crystallography to study chromophore-protein and inter-domain interactions that lead to active states in these proteins.



Amber pic

Amber Bonds

Program/Dates supported: Chemistry/ 2014 - 2016

Title:   Understanding the role of post-translational modifications on cholesterol utilization in  Mycobacterium tuberculosis

Tuberculosis, the disease caused by  Mycobacterium tuberculosis, is the second leading cause of death worldwide. Recent years have witnessed increased incidences of drug resistant strains; demonstrating the imperative need for new antibiotics.  M.tbcholesterol utilization has great potential as a new therapeutic target.  During the course of infection,  M.tb resides in the lipid-rich environment of foamy macrophages which contain cholesterol and cholesterol esters. To adapt to this lipid-rich environment,  M.tbupregulates genes involved in lipid metabolism. The Sampson laboratory has elucidated the mechanisms of cholesterol degradation and extensively characterized a class of cholesterol degradative enzymes known as acyl-CoA dehydrogenases (ACADs). Aside from transcriptional regulation, it is suggested that  M.tb can regulate metabolic flux through post translational modifications (PTMs). PTMs have been shown to negatively regulate the activity of various enzymes. A newly identified PTM, succinylation, occurs extensively in  M.tb and 19 of the cholesterol metabolizing enzymes have been identified as targets of succinylation. This work investigates the effects of succinylation on cholesterol utilization in  M.tb and demonstrates the succinylase activity of a previously annotated acetyl-transferase, Nat. This data suggests that succinylation plays a significant role in the regulation of cholesterol utilization by  M.tb during the course of infection. 


Alyssa  Alyssa Preston

Program/Dates supported on the NIGMS Grant: Chemistry/ 2014-2016

Title: Tracing the brain’s neural circuitry with small molecule probes.

The brain functions by using neurons that link together through synaptic connections to form neural circuits.  Discovering the structure of these circuits is extremely challenging, partly because of the limited number of techniques available for visualizing their anatomy. The most powerful existing strategies employ viruses and lectins that can move across the synapse, allowing one to visualize neural circuits if the virus or lectin is tagged with a fluorophore. However, these viruses and lectins are only applicable to limited species, sluggish in their labelling of neural circuits, and not easily modified to improve their functions.  My research focuses on the design and synthesis of small-molecule probes for use as trans-synaptic tracers of neural circuitry.  In order to design these molecules, I take advantage of the feature of trans-synaptic lectins that enables them to cross the synapse: their affinity for sugars at the cell surface. I hypothesize that small molecules with sugar binding properties similar to trans-synaptic lectins will be able to cross the synapse.  I have recently completed the synthesis of a model fluorescent molecule with high sugar affinity, and I am currently exploring its ability to trace neural circuits in the olfactory system of larval zebrafish. 
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  Zach pic Zachary Ridgway

Program/Dates supported on the NIGMS Grant: Chemistry/ 2014-2016

Title: Design and analysis of soluble IAPP analogs that act as amyloid inhibitors

Type II diabetes (T2D) is a disease that affects 6.0% of the world’s adult population. With no cure, there is a need to expand current methods of treatment. Upon the onset of T2D, a peptide hormone called IAPP (Islet amyloid polypeptide) misfolds to form insoluble fibrils. The aggregation of IAPP is associated with a decrease in beta cell mass and insulin production, contributing greatly to the progression of the disease. Soluble analogs of IAPP have been explored as a platform for therapeutic applications. By making key substitutions to the sequence of human IAPP, a class of analogs is created that act as inhibitors of IAPP aggregation.  My research focuses on understanding the mechanisms by which these analogs inhibit cytotoxicity, through experimental and computational approaches. This will create a better understanding of the toxic intermediate species formed by IAPP, as well as determine criteria for designing more effective inhibitors.

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

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