Self-assembly of model short triblock amphiphiles in dilute solution

In this work, a molecular theory is used to study the self-assembly of short diblock and triblock amphiphiles, with head-tail and head-linker-tail structures, respectively. The theory was used to systematically explore the effects of the molecular architecture and the affinity of the solvent for the linker and tail blocks on the relative stability of the different nanostructures formed by the amphiphiles in dilute solution, which include spherical micelles, cylindrical fibers and planar lamellas. Moreover, the theory predicts that each of these nanostructures can adopt two different types of internal organization: (i) normal nanostructures with a core composed of tail segments and a corona composed of head segments, and (ii) nanostructures with a core formed by linker segments and a corona formed by tail and head segments. The theory predicts the occurrence of a transition from micelle to fiber to lamella when increasing the length of the tail or the linker blocks, which is in qualitative agreement with the geometric packing theory and with experiments in the literature. The theory also predicts a transition from micelle to fiber to lamella as the affinity of the solvent for the tail or linker block is decreased. This result is also in qualitative agreement with experiments in the literature but cannot be explained in terms of the geometric packing theory. The molecular theory provides an explanation for this result in terms of the competition between solvophobic attractions among segments in the core and steric repulsions between segments in the corona for the different types of self-assembled nanostructures.Fil: Zaldivar, Gervasio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Samad, M. B.. University of Nebraska; Estados UnidosFil: Conda Sheridan, Martin. University of Nebraska; Estados UnidosFil: Tagliazucchi, Mario Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentin

Self-Assembled Nanostructures of Peptide Amphiphiles: Charge Regulation by Size Regulation

Self-assembled nanostructures of peptide amphiphiles (PAs) with molecular structures C16K2 and C16K3 (where C indicates the number of carbon atoms in the alkyl chain and K is the lysine in the head group) were studied by a combination of theoretical modeling, transmission electron and atomic force microscopes, and acid-base titration experiments. The supramolecular morphology of the PAs (micelles, fibers, or lamellas) was dependent on the pH and ionic strength of the solution. Theoretical modeling was performed using a molecular theory that allows determining the equilibrium morphology, the size, and the charge of the soft nanoassemblies as a function of the molecular structure of the PA, and the pH and salt concentration of the solution. Theoretical predictions showed good agreement with experimental data for the pH-dependent morphology and size of the nanoassemblies and their apparent pKa's. Two interesting effects associated with charge regulation mechanisms were found: first, ionic strength plays a dual role in the modulation of the electrostatic interactions in the system, which leads to complex dependencies of the aggregation numbers with salt concentration; second, the aggregation number of the nanostructures decreases upon increasing the charge per PA. The second mechanism, charge regulation by size regulation, tunes the net charge of the assemblies to decrease the electrostatic repulsions. A remarkable consequence of this behavior is that adding an extra lysine residue to the charged region of the PAs can lead to an unexpected decrease in the total charge of the micelles.Fil: Zaldivar, Gervasio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Vemulapalli, Sridhar. University Of Nebraska Medical Center; Estados UnidosFil: Udumula, Venkatareddy. University Of Nebraska Medical Center; Estados UnidosFil: Conda Sheridan, Martin. University Of Nebraska Medical Center; Estados UnidosFil: Tagliazucchi, Mario Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentin

Characterization of MAS1-86 Activity in Malaria Parasites

In 2019, ~ 229 million malaria cases were reported globally, causing 409,000 deaths. Malaria is caused by the Plasmodium parasite with cyclical infection in human and Anopheles mosquito host. P. falciparum is the most common species, causing approximately 75% of malaria. Asexual, blood stage parasites cause malaria symptoms. The lifecycle begins with merozoites that invade red blood cells and they develop into rings, then trophozoite, and mature into schizonts. Artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated falciparum malaria. Resistance to all artemisinin (ART) is a widespread problem, which is conferred by point mutations in Kelch 13. The K13C580Y mutation is the most abundant in SE Asia. P. falciparum’s apicoplast, an essential organelle that generates fatty acids, heme, and isoprenoid precursors, is a promising drug target since humans lack this organelle. The apicoplast’s primary function in asexual life stages is to produce isoprenoid precursor isopentenyl phosphate (IPP) via the methylerythritol phosphate (MEP) pathway. IPP supplementation has been shown to chemically rescue MEP inhibited cultures. Delayed death phenotype is defined as growth of treated parasite is unaffected, but growth arrest is observed in the progeny. This is seen when apicoplast biosynthesis and apicoplast metabolic pathways are inhibited. The apicoplast-located PfClpC/P complex degrades proteins and has chymotrypsinlike proteolytic activity. PfClpC is a chaperone to the PfClpP protease. P. falciparum 26S proteasome is a cytoplasmic protease with β1, β2, and β5 subunits that have caspase-like, trypsin-like and chymotrypsin-like activity, respectively. WLL, a proteasome inhibitor, targets the β2 and β5 subunits. An analog of MAS1-86 effectively inhibited multi-drug resistant Staphylococcus aureus ClpX, a homolog of PfClpC, in multi-drug resistant S. aureus. Analogs of MAS1-86 were then tested against P. falciparum and MAS1-86 was identified as the most potent inhibitor. We show that MAS1-86 selected parasites display a 6 - 23-fold increase in resistance to MAS1-86. IPP failed to rescue MAS1-86 parasite inhibition nor did MAS1-86 inhibition display a delayed death phenotype, defined as a 10-fold reduction in IC50 values at 120 hours compared to72 hours. We conclude that MAS1-86 does not target the MEP pathway. MAS1-86 inhibition caused a delay in late trophozoite stages through schizont stages, with fewer nuclei observed in schizonts. This observation is of interest since aberrant scizont morphology with fewer nuclei has been reported in auto-inhibited ClpC P. falciparum. There was no shift in the K13 mutant dose response curves, thus K13 haplotype does not influence parasite susceptibility to MAS1-86. MAS1-86-resistant parasites did not show cross-resistance to proteasome β2 and β5 subunit inhibitor, WLL, which has the same chymotrypsin-like activity as ClpP.https://digitalcommons.unmc.edu/surp2021/1052/thumbnail.jp

Conformal Electrodeposition of Antimicrobial Hydrogels Formed by Self-Assembled Peptide Amphiphiles

The colonization of biomedical surfaces by bacterial biofilms is concerning because these microorganisms display higher antimicrobial resistance in biofilms than in liquid cultures. Developing antimicrobial coatings that can be easily applied to medically-relevant complex-shaped objects, such as implants and surgical instruments, is an important and challenging research direction. This work reports the preparation of antibacterial surfaces via the electrodeposition of a conformal hydrogel of self-assembling cationic peptide-amphiphiles (PAs). Hydrogels of three PAs are electrodeposited: C16K2, C16K3, and C18K2, where Cn is an alkyl chain of n methylene groups and Km is an oligopeptide of m lysines. The processing variables (electrodeposition time, potential, pH, salt concentration, agitation) enable fine control of film thickness, demonstrating the flexibility of the method and allowing to unravel the mechanisms underlying electrodeposition. The electrochemically prepared hydrogels inhibit the growth of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa in agar plates, and prevent the formation of biofilms of Acinetobacter baumannii and P. aeruginosa and the formation of A. baumannii colonies in solid media. C16K2 and C16K3 hydrogels outperform the antimicrobial activity of those of C18K2 while maintaining good compatibility with human cells

Design, Biological Evaluation, and Computer-Aided Analysis of Dihydrothiazepines as Selective Antichlamydial Agents

Chlamydia trachomatis (CT) causes the most prevalent sexually transmitted bacterial disease in the United States. The lack of drug selectivity is one of the main challenges of the current antichlamydial pharmacotherapy. The metabolic needs of CT are controlled, among others, by cylindrical proteases and their chaperones (e.g., ClpX). It has been shown that dihydrothiazepines can disrupt CT-ClpXP. Based on this precedent, we synthesized a dihydrothiazepine library and characterized its antichlamydial activity using a modified semi-high-throughput screening assay. Then, we demonstrated their ability to inhibit ClpX ATPase activity in vitro, supporting ClpX as a target. Further, our lead compound displayed a promising selectivity profile against CT, acceptable cytotoxicity, no mutagenic potential, and good in vitro stability. A two-dimensional quantitative structure–activity relationship (2D QSAR) model was generated as a support tool in the identification of more potent antichlamydial molecules. This study suggests dihydrothiazepines are a promising starting point for the development of new and selective antichlamydial drugs

Synthesis and Antichlamydial Activity of Molecules Based on Dysregulators of Cylindrical Proteases

Chlamydia trachomatis is the most common sexually transmitted bacterial disease globally and the leading cause of infertility and preventable infectious blindness (trachoma) in the world. Unfortunately, there is no FDA-approved treatment specific for chlamydial infections. We recently reported two sulfonylpyridines that halt the growth of the pathogen. Herein, we present a SAR of the sulfonylpyridine molecule by introducing substituents on the aromatic regions. Biological evaluation studies showed that several analogues can impair the growth of C. trachomatis without affecting host cell viability. The compounds did not kill other bacteria, indicating selectivity for Chlamydia. The compounds presented mild toxicity toward mammalian cell lines. The compounds were found to be nonmutagenic in a Drosophila melanogaster assay and exhibited a promising stability in both plasma and gastric fluid. The presented results indicate this scaffold is a promising starting point for the development of selective antichlamydial drugs.Fil: Seleem, Mohamed A.. University Of Nebraska Medical Center; Estados UnidosFil: Rodrigues de Almeida, Nathalia. University Of Nebraska At Omaha; Estados UnidosFil: Chhonker, Yashpal Singh. University Of Nebraska Medical Center; Estados UnidosFil: Murry, Daryl J.. University Of Nebraska Medical Center; Estados UnidosFil: Guterres, Z. R.. Universidade Federal do Mato Grosso do Sul; BrasilFil: Blocker, Amanda M. Southern Illinois University Carbondale; Estados UnidosFil: Kuwabara, Shiomi. Southern Illinois University Carbondale; Estados UnidosFil: Fisher, Derek J.. Southern Illinois University Carbondale; Estados UnidosFil: Leal, Emilse Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Martinefski, Manuela Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Monge, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Ouellette, Scot. University Of Nebraska Medical Center; Estados UnidosFil: Conda-Sheridan, Martin. University Of Nebraska Medical Center; Estados Unido

Design and synthesis of phenazines and indenoisoquinolines as cancer chemopreventive agents

Cancer is the second leading cause of death in the US and worldwide. Even when several efforts have been made and much has been achieved the number of cancer cases is increasing across the globe. The mortality rates of some types of cancer still remain prohibitively high. Therefore, it would be desirable to find a more effective way to deal with the disease. A prevention approach would be ideal to eliminate or reduce he carcinogenesis problem. Chemoprevention aims to stop, delay or reverse the initiation and progression of cancer. This thesis focuses on the design and synthesis of phenazines and indenoisoquinolines as new chemopreventive agents. Not much work in the chemoprevention field has been made using these molecular entities; therefore, the research presented here is exploratory in nature. Various compounds have been synthesized and their SAR studied against a panel of chemopreventive targets. The phenazines were investigated against quinone reductases 1 and 2, inducible nitric oxide synthase and NFkB. The indenoisoquinolines were tested against quinone reductase 1, retinoid X receptor, and NFkB. The synthesis and biological evaluation of a phenazine natural product and its analogues is presented. The preparation of novel indenoisoquinolines bearing acidic, ester, cyano and halide moieties is described. Some key structural features for RXR transcriptional activation and NFκB inhibition are described. Finally, some of the prepared indenoisoquinolines were evaluated against two other targets: tyrosylphosphodiesterase 1 and topoisomerase 1. A basic SAR study of the compounds against these targets is presented

Twisting of Charged Nanoribbons to Helicoids Driven by Electrostatics

Charged amphiphiles in solution usually self-assemble into flat nanoribbons that spontaneously twist into different shapes. The role of electrostatics in this process is still under strong debate. This work studies the electrostatic free energy of twisting a nanoribbon at the level of the nonlinear Poisson−Boltzmann approximation. It is shown that helicoid-shaped ribbons are more stable than flat ribbons, while other shapes under consideration (cylindrical helixes and bent ribbons) are always less stable than the flat ribbon. The unexpected electrostatics-driven twisting of the ribbon into a helicoid is ascribed to the increase in its perimeter with increasing degree of twisting, as charges near the edge of the ribbon are electrostatically more stable than those near its center. This argument successfully explains the effects of salt concentration and the width of the ribbon on the optimal twisting period and allows us to approximately describe the problem of ribbon twisting in terms of two dimensionless variables that combine the helicoid twisting period, the Debye length of the solution, and the width of the ribbon. The magnitude of the electrostatic twisting energy predicted by our calculations is comparable to that of restoring elastic forces for typical ribbons of self-assembled amphiphiles, which indicates that electrostatics plays an important role in determining the equilibrium shape of charged nanoribbons.Fil: Zaldivar, Gervasio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Conda Sheridan, Martin. University of Nebraska; Estados UnidosFil: Tagliazucchi, Mario Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentin