Oral Presentations:
| Presenter (PI) | Title | Abstract |
| Isaac Angera (Del Valle) | Structure-based design of seed-competent proteomimetic macrocycles derived from 4R tauopathic folds | Tauopathies are a class of neurodegenerative disorders whose predominant feature is tau protein deposits in the brain. Identification of the minimal epitopes of tau required for transcellular propagation represents a key step toward more relevant models of disease progression. We implement a diversity-oriented peptide macrocyclization approach toward seed-competent miniature tau, or “mini-tau”, proteomimetics. |
| Haylie Hennigan (Parkinson) | Synthesis of butenolide signaling molecules from Streptomyces spp. | Bacterial natural products are an important source of medicines, but many biosynthetic gene clusters that produce potentially novel, bioactive natural products are cryptic. We are synthesizing butenolide quorum sensing molecules that can activate these clusters, enabling access to novel natural products |
| Ginny Kim | Diazo mediated metal carbenoid construction of oxepino[b]indoles | Diazo mediated metal carbenoid oxepino[b]indoles were rapidly constructed by exploiting the orthogonal pi bonds of vinyl allenes in a net [4+3] cycloaddition with readily accesible diazo oxindoles. Moreover, exposure of the oxepino[b]indole to either an acid or base promoted a facile ring contraction event to afford functionalized spiropentyl oxindoles. |
| Katrina Holly (Flaherty) | Development of selective carbonic anhydrase inhibitors to treat Enterococcal infections | Bacterial carbonic anhydrase inhibitors have shown efficacy in animal models of enterococcal infections. Work presented will describe progress toward widening the selectivity window over human carbonic anhydrase enzymes. |
| Michael Serwetnyk | Enniatin A is a Hsp90 Inhibitor that Stimulates the Immune System against Triple-negative Breast Cancer | TBA |
| Laura Sanford (Davisson | Optimization and Evaluation of Diphyllin-Derived Antivirals | Diphyllin and its derivatives have been shown to be useful in vitro and in vivo for inhibition of viral entry for a number of viruses. Here, we show potency improvement and promising pharmacokinetics for oral delivery in the context of Ebola virus. |
| Amr El-Araby | Reconstitution of the Cytoplasmic Cell-Wall-Recycling Events of Pseudomonas aeruginosa | The Gram-negative bacterium Pseudomonas aeruginosa recycles its peptidoglycan degradation products which enables its resistance to various classes of antibiotics. I present the reconstitution of the recycling pathway in vitro. The reconstituted pathway is developed for inhibitor screening. |
| Desmond Akwata (Sintim) | Novel Tak1 inhibitors for cancer and inflammatory diseases | Transforming growth factor-β-activated kinase 1 (TAK1) regulates cell death and inflammatory pathways. Many Tak1 inhibitors have been described but none has been shown to have the right combinations of potency, kinome selectivity and oral bioavailability for clinical translation. Here, we describe novel orally bioactive Tak1 inhibitors, which have shown efficacies against various cancer and arthritis disease models. |
Poster Session 1: Friday Oct. 18th, 8:30-9:30pm
| Presenter | Title | Abstract |
| Qiuyun Yang | A Scalable Synthesis of Bulgecines, the Core Pharmacophore in Bulgecins | The simultaneous inhibition of LTs by a bulgecin and penicillin-binding-proteins (PBPs) by a beta-lactam results in bulge formation at bacterial sites of septation, which leads to lysis. Mechanistic and structural studies of bulgecin A and two LTs in Pseudomonas aeruginosa, MltD and Slt, reveals that the pyrrolidine core of bulgecins (named bulgecinine) mimics the transition-state oxocarbenium within the active site. |
| Kejia Shi | Cucurbit[7]uril Encapsulation Stabilizes Imines in Weak Acid | The rapid hydrolysis of imines severely limits their use in drug discovery and material development. Herein, we report a new strategy to significantly prolong the lifetime of imines via supramolecular encapsulation. Imines with p-dimethylamino benzaldehyde motif can form tight and stable complexes with CB7 in weak acid with inhibited hydrolysis. |
| Andrew Gutierrez | Development and Evaluation of a Novel Fluorescence Tagged TRAP1 Inhibitor | TBA |
| Carlos Cal y Mayor Luna | Elucidation of Spore Germination of Clostridioides difficile | We study the Csp proteins that control the germination process of Clostridioides difficile. Here, we present the oligomer state of the Csp proteins and, the first biochemical evidence regarding the quantitative binding of germinants to the Csp proteins and the protein-protein interactions among them. |
| Tyelor Reynolds | Hsp90 Beta-selective inhibitors as a safer therapeutic alternative | Hsp90 pan-inhibitors have been investigated in the clinic for their potential use as anti-cancer therapeutics. However, their progress has been limited primarily by on-target side effects and dose-limiting toxicities. As an alternative strategy, Hsp90 beta-selective inhibitors maintain efficacy while avoiding the on-target complications associated with the inhibition of Hsp90 alpha. |
| Kevin Catalfano | Optimization of Hsp90/Aha1 small molecule disruptors for the treatment of tauopathy | Recently, we used the small molecule disruptor of Hsp90/Aha1, KU-177, as a lead compound, then we synthesized and evaluated derivatives for their ability to disrupt Hsp90/Aha1 interactions and block Hsp90/Aha1 driven P301L tau aggregation in ThT assays. Preliminary structure-activity relationships were revealed, which led to identification of a new lead compound, ND-AHA-46, that contains a cis-like amide bond. ND-AHA-46 retains activity as a Hsp90/Aha1 disruptor in both SH-SY5Y and SK-BR-3 cells without direct inhibition of Hsp90, and thus represents a new scaffold for drug discovery optimization. This new lead was pursued through a series of analogs probing the central amide for necessary geometry and ideal heteroatom substituents, wherein the results of this study yielded compounds with improved efficacy and physiochemical properties such as half-life and aqueous solubility. |
| Bernice Webber | Polymer Nanoparticle Hydrogel System for Ultra-Long Insulin Delivery | The need for long-acting insulins has led to advancements in insulin analogs such as insulin glargine and the exploration of long-term delivery platforms. This project expands on the slow dissolution of insulin glargine through a two-step degradation system to allow for an ultra-long-acting insulin release platform where insulin is loaded into polymeric nanoparticles (NPs), which are then used as a cross-linker to form a hydrogel. By imposing two forms of degradation to overcome before insulin release, this system better maintains basal insulin levels over extended periods, minimizing injection frequency and promoting patient adherence to treatment regimens, thus addressing a key challenge in the adequate management of diabetes. |
| Amr El-Araby | Reconstitution of the Cytoplasmic Cell-Wall-Recycling Events of Pseudomonas aeruginosa | The Gram-negative bacterium Pseudomonas aeruginosa recycles its peptidoglycan degradation products which enables its resistance to various classes of antibiotics. I present the reconstitution of the recycling pathway in vitro. The reconstituted pathway is developed for inhibitor screening. |
| Van T. Nguyen | Restoring susceptibility to beta-lactam antibiotics in methicillin-resistant Staphylococcus aureus | Infections by Staphylococcus aureus have been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureus by acquisition of the bla and mec operons. The presence of the β-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4 is covalently engaged with the active-site serine of BlaR. Compound 4 potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureus strains. The combination of 4 with oxacillin or meropenem shows efficacy in infected mice, validating the strategy. |
| Trevor Trombley | Structure-Based Drug Design of α-Amino-β-carboxymuconate-ε-semialdehyde Decarboxylase Inhibitors as Novel Promoters of NAD+ Biosynthesis | The α-Amino-β-carboxymuconate-ε-semialdehyde decarboxylase enzyme (ACMSD) is a key kynurenine pathway enzyme involved in the biosynthesis of NAD+, a ubiquitous enzyme co-factor implicated in aging, energy metabolism, DNA repair, and gene expression, among other cellular processes. Our group identified Diflunisal as a putative inhibitor of ACMSD (IC50 = 13.5 µM) and employed structure-based drug design principles to reveal an improved understanding of the key pharmacophore and deliver a series of 6-halo-5-naphthyl salicylates with IC50 values of 600 – 650 nM, representing a 20-fold improvement in inhibitory potency relative to Diflunisal. |
| Abdulrahman Moursy | Synthesis and Development of Selective δ-Opioid Receptor Agonists | DOR agonists show promise for treating various clinical disorders, but current options lack efficacy or cause severe side effects. Our goal is to develop selective DOR agonists with improved safety and efficacy. |
| Namuunaa Otgontseren | Syntheses of furanone natural products and signaling hormones from Streptomyces avermitilis and Delisea pulchra | We have developed diversifiable syntheses of the quorum sensing molecule, avenolide, from Streptomyces avermitilis and the defensive halogenated furanones from Delisea pulchra. Both molecules are challenging to access from their native hosts, either being produced in very low titers or coming from difficult to source organisms, making a synthetic route essential to further study their bioactivities. |
| Jude Quarshie | SWI/SNF inhibitors for cancer treatment | BD98 is an inhibitor of the SWI/SNF chromatin remodeler with activity against prostate cancer; however, its mechanism of action is unknown. We are using genetic and chemical biology approaches to elucidate the exact biochemical target of BD98 within SWI/SNF complexes. |
| Joshua Kaiser | New kinase inhibitors synthesized via multi-component reactions | Protein kinases play important roles in health and disease and many protein kinase inhibitors have been approved by the FDA. While there are over 500 kinases in human cells, only a handful have been successfully drugged. Using multi-component chemistries, we have synthesized novel KIs that target kinases that play roles in cancer progression, yet have not been drugged in the clinic, such as CLKs and Haspin kinases. |
| Menna Shalaby | Pharmacological validation of AspC for the treatment of tuberculosis | The alanine aminotransferse (AspC) from Mycobacterium tuberculosis is a potential therapeutic target. The research will present the first inhibitors of the enzyme along with anti-tubercular activity. |
Poster Session 2: Saturday Oct. 19th, 11:00am-12:00pm
| Presenter | Title | Abstract |
| Shadwa Eldosuky | Flow Synthesis of Aripiprazole | Aripiprazole has been prepared efficiently in flow via a three-step sequence using microchip reactors. |
| Dr. Jo Davisson | Metallodrugs for Cyanide Antidotes | We have started optimization of platinum agents to counteract the effects of cyanide poisoning. |
| Anthony Mena Nils Balegamire | Tetrahedral Molecular Cages for Selective Catalysis | This presentation will describe new advances in utilizing tetrahedral molecular cages as catalysts for the synthesis of precision polymers, which are currently being developed as next-generation polymer-protein drug conjugates to improve the formulation and delivery of protein drugs. |
| Dr. Kyle Colston | New Insight into the Mechanism of Oral Peptide Formulations | This presentation will describe new mechanistic insight into the oral absorption of polar peptide drugs in the presence of permeation enhancers. Our results provide valuable insight to help guide the rational design of new oral peptide drug formulations in the future. |
| Ryan Herrick | Diselenide-Enabled Photocatalytic Hydrofunctionalization of gem-Difluoroalkenes | A photocatalytic method simplifies access to medicinally relevant difluoroalkyl ethers and azoles through the coupling of gem-difluoroalkenes with alcohols or azoles. Notably, an uncommon diselenide co-catalyst is essential to enhance selectivity for the desired hydrofunctionalization processes. |
| Austin Zhao | A Deoxyfluoroalkylation Strategy to Access Highly Substituted Trifluoromethylated Arenes and Heteroarenes | Trifluoromethyl arenes (Ar–CF3) are amongst the most commonly encountered fluorinated substructures in pharmaceutical, agrochemical, and material sciences; however, predominant methods to access Ar–CF3 possess several limitations that restricts access to desirable highly functionalized Ar–CF3-containing compounds. To expand the scope of accessible Ar–CF3-based molecules, we present an innovative and orthogonal deoxyfluoroalkylation/aromatization approach that exploits readily accessible and programable cyclohexan(en)one substrates to deliver highly functionalized Ar–CF3 compounds in a one/two-pot sequence. |
| Kyle Faivre | Precision Supramolecular Chemistry Tools for Pharmaceutical Protein Biotechnology | This presentation will discuss recent progress in the Schneebeli lab in advancing precision supramolecular probes and catalysts for pharmaceutical protein biotechnology. Specifically, our supramolecular probes are designed to enable high-throughput in vivo selection of peptide drugs in the future, to advance the discovery of permeable and stable peptide drug candidates. |
| Gihan Perera | Structural and Biophysical Characterization of TCR-Recognition and Immunogenicity of Public Neoantigens Derived from Mutated NRAS | T cells receptors (TCRs) mediate T-cell anti-tumor immune responses through the recognition of mutation-derived cancer-specific peptides (referred to as neoantigens) presented by major histocompatibility complex (MHC) proteins. The current study aims to characterize the basis of the specificity and cross reactivity of a panel of patient derived TCRs that recognize NRAS Q61-derived neoantigens. X-ray crystal structures and molecular dynamics simulations of NRAS Q61 peptide/MHC complexes depict several distinguishable features between neoantigens and their WT counterpart which could promote neoantigen-specific interactions with incoming TCRs. |
| Sebastian Pardo | Synthesis of Tumor-Targeting IRE-1 Inhibitors for B-cell Cancer Therapy | The IRE-1 kinase/RNase processes XBP-1 mRNA into its spliced form (XBP-1s), which is crucial for the survival of of B-cell leukemia, lymphoma, and multiple myeloma. The inhibitor B-I09, a prodrug with an aldehyde-masking group, effectively suppresses XBP-1s in multiple myeloma cells. We have modified the structure of B-I09 to incorporate sensitive groups that react under reactive oxygen species or reductive/thiol conditions, aiming to improve tumor targeting efficiency and adjust the stability. We are also developing a new B-I09 analog with the same advantage and that may be combined with a CD20 nanobody to improve targeting of lymphocytic leukemia cells. |
| Jingdong Yang | Targeting mSleC and CspB to Inhibit Spore Germination in Clostidioides difficile Infection | Through the evaluation of a library containing 120 oxadiazoles, we delineate the structure-activity relationship of these inhibitors. Among the oxadiazoles tested, compound 106 (5-(4-(Aminomethyl) phenyl)-3-(2-(4-(trifluoromethyl) phenoxy) pyridin-4-yl)-1,2,4-oxadiazole) emerges as the most potent one, with an IC50 of 6 ± 0.4 μg/mL and 10 times higher selectivity compared with the previous hit compound. Furthermore, we elucidate the mechanism of action of compound 106, revealing its dual target proteins, mature SleC (Kd =12 ± 1.0 μM) and CspB (Kd = 8.0 ± 1.0 μM). |
| Michael Serwetnyk | TBA | TBA |
| Ethan Burghardt | Towards Bioorthogonal (-)Zampanolide Analogues: Tools for studying the cytoskeleton | The polyketide natural product, zampanolide, exhibits potent cytotoxicity by binding to the taxane site, stabilizing microtubules. Conformation-activity relationship study has enabled the discovery of simplified analogues that retain activity. This work aims to synthesize a simplified analogue which contains a bioorthogonal handle for live-cell imaging. |
| Monika Stefanik | Identification of Small Molecules Targeting Penicillin Binding Protein 4 in Methicillin-Resistant Staphylococcus Aureus | Antibiotic resistance is a well-established global health threat. Although the introduction of new antibiotics has historically been employed to combat multidrug resistant pathogens, the rapid development of antibiotic resistance coupled with Big Pharma’s exit from antibiotic development has prompted the investigation of orthogonal approaches to address resistant bacteria. Penicillin binding protein 4 (PBP4) is a key determinant of Staphylococcus aureus resistance to fifth-generation cephalosporins (ceftobiprole and ceftaroline) and is essential for osteomyelitis, which is a chronic disease characterized by recurring bacterial invasion of the cortical bone osteocyte lacuno-canalicular network (OLCN). From these perspectives, the development of S. aureus PBP4 inhibitors may represent dual functional therapeutics that prevent osteomyelitis, and reverse PBP4-mediated antibiotic resistance. A high-throughput screen for small molecules that inhibit S. aureus PBP4 function identified a potential benzothiophene adjuvant scaffold. We present a preliminary structure activity relationship (SAR) study on the benzothiophene scaffold, identifying several compounds with increased PBP4 inhibitory activity, some of which also inhibit PBP2a. |
| Eva Amatya | Development of Hsp90 C-terminal Inhibitors: To Treat 2 Diseases with 1 Target | TBA |
| Hao Xu | Development of a New Generation of Grp94-seletive Inhibitors | TBA |