Retirement Symposium In Honor of Professor Carol M. Taylor
Friday, November 22, 2019
Life Sciences Annex A101
Carol Taylor received her BSc in 1987, and her MSc in 1988 from the University of Auckland, New Zealand. Her research at the University of Auckland, with Professor Con Cambie, involved the synthesis of ambergris odorants employing New Zealand natural products as starting materials. In 1987 and 1988 Carol spent two summers investigating the chemistry of ortho-quinone monoimides with Professor Harold W. Heine of Bucknell University (PA, USA). She received her PhD in 1993 from the University of Pennsylvania (USA) under the direction of Professor Ralph Hirschmann and Professor Amos B. Smith, III. Her Ph.D. thesis involved the development of catalytic antibodies for peptide bond formation. From 1993 to 1994, Carol was a Research Associate at Princeton University (NJ, USA) with Professor Dan Kahne, working in the area of solid phase oligosaccharide synthesis. In 1995 Carol returned to New Zealand to the position of Lecturer at the University of Auckland. In April 2000, she moved to Massey University as a Senior Lecturer and was promoted to Associate-Professor in 2003. In 2001, she received the RSC/NZIC Easterfield Award for original contributions by a New Zealand chemist under the age of 35. In July 2006 she returned to the USA as Associate Professor at Louisiana State University in Baton Rouge. She was promoted to Professor in 2012 and became the William and Patricia Senn, Jr, Distinguished Professor in 2017. She served her Department as Associate Chair (2012-13) and Chair (2015-18). She was Interim Associate Dean for Research & Administration in LSU’s College of Science from February to July 2019. Her research program has been engaged primarily with the chemical synthesis of novel peptide motifs that arise via post-translational modifications and non-ribosomal peptide synthesis. In 2020, she will return to New Zealand to address her work-life balance.
Symposium Program (Click Name for Title and Abstract)
Title: Suppressing Termination Events in the Ring-Opening Polymerizations of Amino-Acid Derived N-thiocarboxyanhydrides towards Well-defined Polypeptides.
Abstract: Amino acid-derived N-thiocarboxyanhydrides (NTAs) are attractive substrates for polymerization to access polypeptides due to their enhanced thermal and hydrolytic stability relative to the N-carboxyanhydride (NCAs) counterparts. However, in contrast to NCAs, polymerizations of NTAs are challenging. Early reports on the polymerization of NTAs all resulted in low conversion regardless of the monomer structures. Previously, we reported a controlled polymerization of NTAs that proceed by normal amine mechanism (NAM) can be achieved by accelerating the release of carbonyl sulfide (COS) thus suppressing termination events (i.e., isocyanate formation by the release of hydrogen sulfide) in low polarity solvent (e.g., hexanes or heptane). The use of low polarity solvent results in heterogeneous reactions where both the monomer and polymer products have limited solubility resulting in molecular weight broadening due to the restricted access to the growing chain ends. Recently, I demonstrated the potential to synthesize polypeptides with controlled molecular weights and narrow molecular weight distribution (PDI < 1.1) in a homogenous solution using a polar solvent (i.e. CH2Cl2) at room temperature with the incorporation of a weak organic acid (e.g., acetic acid) in conjunction with a primary amine initiator. The weak acid is proposed to promote the polymerization of NTAs by accelerating the elimination of COS from the carbamate propagating intermediate to form the active amino propagating species and reducing side reactions by modulating the relative abundance of the active amino propagating species via acid−base equilibrium.
Title: Chemoselective Cyclization of Epoxyketones to Epoxonium ions by Bronsted Acids, Enabling Regioselective Ring Opening.
Abstract: Epoxonium ions are strained-bicyclic electrophiles that are generated by umpoling the electrophilic reactivity of an epoxide to nucleophilic reactivity. These putative oxonium ions are then poised to nucleophilic capture leading to regioisomeric endocyclic or exocyclic mixtures. Recently in our lab, we have uncovered a new epoxonium ion cyclization strategy which proceeds through regioselective ring opening of the epoxonium ion, leading to exocyclic products. By subjecting unactivated epoxyketones to mixtures of triphosgene and pyridinium sulfonate acid, we observe the formation of tetrahydropyranoside (THP) products via exocyclic capture of the epoxonium ion intermediate by chloride ions. We are pleased to present our most recent discovery and will disclose a series of THP products; as well as mechanistic details supporting our epoxonium ion cyclization hypothesis. Also, we will discuss a novel sulfonate counterion effect that modulates product selectivity in favor of the THP.
Title: Synthesis and Evaluation of near-IR Boron-Dipyrromethene (BODIPY) Bioconjugates Selectively Targeting Cancers Overexpressing Epidermal Growth Factor Receptor (EGFR)
Abstract: Five boron dipyrromethene (BODIPY) bioconjugates were synthesized to incorporate the epidermal growth factor receptor (EGFR)-targeting peptide 3PEG-LARLLT and/or a glucose or biotin ethylene diamine monomer for the purpose of imaging colon cancers overexpressing EGFR. These bioconjugates were evaluated to determine their photophysical properties and binding affinities for the extracellular domain (ECD) of EGFR using fluorescence microscopy, surface plasmon resonance (SPR), molecular modeling, competitive binding assays, in vitro and in vivo studies. BODIPY bioconjugates containing the EGFR-targeting peptide 3PEG-LARLLT were found to bind specifically to EGFR ECD whereas those bioconjugates without peptide were found to bind non-specifically or weakly. All BODIPY bioconjugates were determined to have low dark- and phototoxicity (IC50 > 94 μM) in human HT-29 cells. In vivo studies using nude mice with subcutaneously implanted human HT-29 xenografts revealed that BODIPY bioconjugates with the EGFR-targeting peptide localized within the tumor xenografts within 24 h of intraveneous injection. The results presented will illustrate that BODIPY bioconjugates containing the EGFR-targeting peptide 3PEG-LARLLT are promising candidates for use as near-IR fluorescent imaging agents for colon cancers overexpressing EGFR.
Title: A Novel Approach to the Synthesis of the Cycloparaphenyleneacetylene (CPPA) Carbon Nanohoops
Abstract: The field of carbon nanohoops has seen great advancements in the past two decades. Due to their radially oriented π system and ring strain, carbon nanohoops found potential applications in organic electronics, sensing and bioimaging. However, large-scale syntheses of carbon nanohoops are often limited by low-yielding macrocyclization. Here, we successfully achieved the preparation of cycloparaphenyleneacetylene (CPPA) nanohoops using alkyne metathesis for macrocyclization in high yields. Also, other new approaches towards more effective high-yielding synthetic methods are being explored.
Title: Development of Engineered Soil Surrogates using Controlled Radical Polymerization
Abstract: Soil is an important environmental component, and the study of soil processes have many practical implications such as improvement in agriculture, mitigation of climate change etc. Study of fate, bioavailability, and transport of pollutants involves molecular level understanding of their interactions with soil. This can be challenging due to complex and heterogeneous nature of soil. One common approach used is the correlation of macroscopic properties of soil, (e.g. sorption) with empirical parameters such as carbon content, elemental ratios etc. While these metrics provide some insight into important soil characteristics, study of in-depth molecular level interactions requires standard soil. Several attempts to synthesize artificial test soil substrates have been proposed to overcome this limitation. However, the exact composition of these “artificial soils” are ill-defined as they use organic components from plant derived materials. This work demonstrates the design and synthesis of Engineered Soil Surrogates (ESSs) using controlled radical polymerization for use in study of geomacromolecular processes such as sorption of Agricultural Chemicals (ACs) into the soil. The initial design of ESSs consisted of mesoporous SiO2 as an inorganic matrix tethered with multi-block oligomers containing alky (tier-1), O-aryl (tier-2) and polar (tier-3) blocks carefully selected to echo hydrophobic, aromatic and hydrophilic components of the Soil Organic Matter (SOM) respectively. A series of ESSs with increasing complexity were used in concert with sorption isotherm data obtained by batch mode experiments using Norflurazon (NOR) as a model AC. As the polarity of the second tier increased, the ability of the ESS to sorb NOR decreased, as was the case when a polar third tier was added, pointing to a largely hydrophobic driving force for NOR adsorption to the ESSs. Hydrogen bonding, pi-stacking, confirmation and hydration were also shown to influence binding of NOR to ESS.
Title: Progress toward the Synthesis of a Pentasaccharide Portion of an A. baumannii Lipooligosaccharide
Abstract: Acinetobacter baumannii is a common cause of infections associated with ICU residence, traumatic injury, mechanical ventilation, and neurosurgery. High percentages of A. baumannii clinical isolates are drug resistant, and “pan-drug-resistant” strains are becoming increasingly common. Because of increasing antibiotic resistance, preventative measures such as vaccine development are important. As an approach to vaccine development, we propose the synthesis of a pentasaccharide portion of an A. baumannii lipooligosaccharide (LOS) to be conjugated to so-called “carrier molecules” for the development of an A. baumannii vaccine. This pentasaccharide consists of sugars like Kdo, D-galactosamine, and N-acetyl-D-glucosaminuronic acid that are absent in humans and therefore likely to be immunogenic. Progress toward the synthesis of the pentasaccharide portion of the proposed glycoconjugate vaccine will be discussed.
Title: Natural peptides to potential therapeutic molecules.
Abstract: Protoxin II (ProTx II) and Mutacin 1140 (MU1140) are naturally occurring polycyclic peptides. ProTx II is a voltage gated sodium channel 1.7 isoform (Nav 1.7) blocker and selective over other sodium channel isoforms. MU1140 is one of lantibiotic that is active against Clostridium Difficile (C. diffile) infection. This presentation will cover the Structure-Activity Relationship (SAR) investigation of two peptides to improve therapeutic profiles.
Title: Computational Investigations of the Mechanism of Regioselective Indole Addition to Unsymmetrical Silyloxyallyl Cations.
Abstract: In this work we probed the mechanism underlying the experimental observations by the Kartika group on the regioselectivity of indole addition to unsymmetrical silyloxyallyl cations. We used a combination of electronic structure calculations (both static and ab initio metadynamics simulations) to determine the reaction pathways, including competing reactions, for this multistep system. The results of this work will be presented.
Title: The Promise of Long-Acting Slow Effective Release Antiretroviral Therapy
Abstract: To ensure efficacy, existing antiretroviral therapy (ART) require life-long adherence to medicines. Limitations of such treatments include shorter drug half-lives, variable pharmacokinetic profiles and inadequate therapy access to cellular and tissue reservoirs of infection, thereby increasing the likelihood of developing drug resistant virus strains. Pill fatigue and adverse drug reactions can negatively impact adherence. We have demonstrated that improved drug half-lives, tissue biodistribution and maintenance of optimal therapeutic drug levels at restricted sites of infection could be realized through cell and tissue targeted long acting slow effective release (LASER) ART delivery systems and by optimizing drug metabolism. Discussion points will highlight LASER ART with a dosing interval goal of once/6-12 months to maximize the effectiveness of pre-exposure prophylaxis and treatment regimen.
Title: Allostery regulates Scc4’s dual functions in Chlamydia trachomatis
Abstract: Chlamydia trachomatis is an oligate intracellular bacteria pathogen responsible for the most common sexually transmitted bacterial disease in the world. The bacterium has a unique bi-phasic developmental cycle with a type III secretion system to invade host cells. Scc4 is a protein that functions both as a type III secretion system chaperone and as an RNA polymerase binding protein to regulate σ66-dependent transcription. Our research groups has worked to determine the high-resolution structure of Scc4 and to understand its binding interactions with its protein partners. As a transcription factor, Scc4 binds the RNAP holoenzyme between σ66 region 4 and the beta flap of the beta subunit. As a type III secretion system chaperone, Scc4 binds its partner protein, Scc1, to chaperone the essential virulence factor, CopN. The structure of the Scc4:Scc1 complex has been a focus of intense study in our laboratory. A mutant of Scc4 was identified that disrupts the Scc4:Scc1 interaction, but maintains Scc4’s ability to bind RNA polymerase holoenzyme.
Title: Thioenamide Synthesis Inspired by Peptide Macrocycles
Abstract: The thioenamide functional group features in several natural products with promising biological activity, including some penicillins, linaridins, and lantibiotics. Notwithstanding its potential importance, the functional group is understudied, with limited methods for synthesis and virtually no information on the functional group’s tolerance to assorted chemically and physiologically relevant conditions. We have reported an acid-promoted route to thioenamides via condensation of an aldehyde (bearing a β-thioether) and a primary amide, to afford moderate yields and high Z-stereoselectivity. Optimization of reactions conditions and a study of protecting group compatibilities, preceded application of the condensation reaction to peptidyl examples. Synthesis of the C-terminal macrocycle of cypemycin was achieved, en route to the first total synthesis of the 22-amino acid peptide.
Title: Disorder Has Its Benefits
Abstract: Early in the 21st century, the startling observation was made that intrinsically disordered domains in proteins are quite abundant, with estimates indicating that up to two-thirds of eukaryotic proteins contain intrinsically disordered regions. Although intrinsically disordered domains (IDDs) are refractory to standard three-dimensional characterization, we have recently utilized small-angle neutron scattering (SANS) to demonstrate a folding-binding reaction in an important pair of circulatory proteins. Vitronectin is an abundant human circulatory protein that is also found in the extracellular matrix of tissues. It is a cofactor for the serine protease inhibitor, plasminogen activator inhibitor type 1 (PAI-1), which is the chief inhibitor of proteases involved in thrombolysis. Vitronectin stabilizes PAI-1 and localizes it to blood clots or inflammatory sites. Our structural and computational studies over the years have identified an intrinsically disordered domain (IDD) in vitronectin. We have now employed contrast-variation SANS experiments and circular dichroism to demonstrate a gain of structure in the vitronectin IDD upon binding to PAI-1. Complementary protein engineering and stopped-flow kinetics were used to define the PAI-1 binding site within the IDD to a short sequence of 24 amino acids. Models for the PAI-1:SMB-IDD complex highlight four ion pairs that bridge the interface between the two proteins; this binding is proposed to lead to the assembly of higher-order structures of PAI-1 and vitronectin commonly found in tissues.
Title: Running Rings Around Peptides at LSU
Abstract: Cyclic peptides are privileged structures in biology and medicine. The constraint of the macrocycle can favor bioactive conformations and the compounds are inherently stabilized toward proteolytic enzymes. Sequences often include D-amino acids and highly modified residues. The synthesis of cyclic peptides is therefore an important but challenging undertaking. This talk will describe the total synthesis of alloviroidin and progress toward the bicyclic skeleton of the theonellamides. Alloviroidin is an actin-binding cyclic heptapeptide isolated from the destroying angel mushroom, Amanita virosa. The theonellamides are a family of bicyclic dodecapeptides with a bridging t-histidinoalanine residue. They are produced by symbiotic bacteria living in marine sponges of the Theonella genus. Theonellamides are potent antifungal agents with a novel mechanism of action.