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

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

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

Novel Marine Phenazines as Potential Cancer Chemopreventive and Anti-Inflammatory Agents

Two new (1 and 2) and one known phenazine derivative (lavanducyanin, 3) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp. (strain CNS284). In mammalian cell culture studies, compounds 1, 2 and 3 inhibited TNF-α-induced NFκB activity (IC50 values of 4.1, 24.2, and 16.3 μM, respectively) and LPS-induced nitric oxide production (IC50 values of >48.6, 15.1, and 8.0 μM, respectively). PGE2 production was blocked with greater efficacy (IC50 values of 7.5, 0.89, and 0.63 μM, respectively), possibly due to inhibition of cyclooxygenases in addition to the expression of COX-2. Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle, as a result of apoptosis. These data provide greater insight on the biological potential of phenazine derivatives, and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects

Control of Peptide Amphiphile Supramolecular Nanostructures by Isosteric Replacements

Supramolecular nanostructures with tunable properties can have applications in medicine, pharmacy, and biotechnology. In this work, we show that the self-assembly behavior of peptide amphiphiles (PAs) can be effectively tuned by replacing the carboxylic acids exposed to the aqueous media with isosteres, functionalities that share key physical or chemical properties with another chemical group. Transmission electron microscopy, atomic force microscopy, and small-angle X-ray scattering studies indicated that the nanostructure's morphologies are responsive to the ionization states of the side chains, which are related to their pKa values. Circular dichroism studies revealed the effect of the isosteres on the internal arrangement of the nanostructures. The interactions between diverse surfaces and the nanostructures and the effect of salt concentration and temperature were assessed to further understand the properties of these self-assembled systems. These results indicate that isosteric replacements allow the pH control of supramolecular morphology by manipulating the pKa of the charged groups located on the nanostructure's surface. Theoretical studies were performed to understand the morphological transitions that the nanostructures underwent in response to pH changes, suggesting that the transitions result from alterations in the Coulomb forces between PA molecules. This work provides a strategy for designing biomaterials that can maintain or change behaviors based on the pH differences found within cells and tissues.Fil: Xing, Huihua. University of Nebraska; Estados UnidosFil: Chin, Stacey M.. Northwestern University; Estados UnidosFil: Udumula, Venkata Reddy. University of Nebraska; Estados UnidosFil: Krishnaiah, Maddeboina. University of Nebraska; Estados UnidosFil: Rodrigues de Almeida, Nathalia. University of Nebraska; Estados UnidosFil: Huck Iriart, Cristián. Universidad Nacional de San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Picco, Agustin Silvio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Lee, Sieun Ruth. Northwestern University; Estados UnidosFil: 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: Jackson, Kelsey A.. 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; ArgentinaFil: Stupp, Samuel I.. Northwestern University; Estados UnidosFil: Conda Sheridan, Martin. University of Nebraska; Estados Unido

Identification, Synthesis, and Biological Evaluation of the Metabolites of 3-Amino-6-(3′-aminopropyl)-5<i>H</i>-indeno[1,2-<i>c</i>]isoquinoline-5,11-(6<i>H</i>)dione (AM6–36), a Promising Rexinoid Lead Compound for the Development of Cancer Chemotherapeutic and Chemopreventive Agents

Activation of the retinoid X receptor (RXR), which is involved in cell proliferation, differentiation, and apoptosis, is a strategy for cancer chemotherapy and chemoprevention, and 3-amino-6-(3′-aminopropyl)-5<i>H</i>-indeno­[1,2-<i>c</i>]­isoquinoline-5,11-(6<i>H</i>)­dione (AM6–36) (<b>3</b>) is among the few RXR ligands known. The presently reported studies of <b>3</b> include its binding to human plasma proteins, metabolic stability using human liver microsomes, metabolism by human liver microsomes and hepatocytes, and in vivo disposition in rat serum, liver, and mammary tissue. Compound <b>3</b> was 75% bound to human plasma proteins, and its metabolic stability was much greater than propranolol. One phase I metabolite was formed by human liver microsomes, seven phase I and II metabolites were formed by human hepatocytes, and five metabolites were detected in rat serum and liver after oral administration. The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NFκB