Observed sea breeze life cycle in and around NYC: Impacts on UHI and ozone patterns

This observational study investigates New York City (NYC) impacts on summer sea breeze fronts (SBFs) during a 2018 LISTOS Campaign day with a regional heat wave and O3 episode. A morning urban heat island peaked at 8.3 °C and then induced convergences into the City, trapping its NO2 emissions. SBFs came ashore at 0700 EST from the Atlantic along southern Long Island (LI), and from the LI Sound along northern LI and southern Connecticut; 2-h later another formed over New Jersey. The Ocean front was retarded over NYC at noon, while all fronts merged by 1400 EST and continued inland for four more hours. High O3 first appeared at 0900 EST downwind of NYC. By 1100 EST, a new surface peak formed north of the City in the Hudson River Valley (HRV). The maxima merged, peaking at 143 ppb at 1300 EST behind the SBF and near the maximum temperatures of 39 °C. Trajectories ending at the northern LI site with a PBL O3 peak first passed NYC, arrived before the episode, and then recirculated back in its SB flow. Trajectories ending in the HRV showed pollutant transport over NYC twice, before advection northward into the narrow Valley by the ocean SBF

Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis

Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments

Corrigendum: Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes

Acanthamoeba species, Naegleria fowleri, and Balamuthia mandrillaris are opportunistic pathogens that cause a range of brain, skin, eye, and disseminated diseases in humans and animals. These pathogenic free-living amoebae (pFLA) are commonly misdiagnosed and have sub-optimal treatment regimens which contribute to the extremely high mortality rates (>90%) when they infect the central nervous system. To address the unmet medical need for effective therapeutics, we screened kinase inhibitor chemotypes against three pFLA using phenotypic drug assays involving CellTiter-Glo 2.0. Herein, we report the activity of the compounds against the trophozoite stage of each of the three amoebae, ranging from nanomolar to low micromolar potency. The most potent compounds that were identified from this screening effort were: 2d (A. castellanii EC50: 0.92 ± 0.3 μM; and N. fowleri EC50: 0.43 ± 0.13 μM), 1c and 2b (N. fowleri EC50s: <0.63 μM, and 0.3 ± 0.21 μM), and 4b and 7b (B. mandrillaris EC50s: 1.0 ± 0.12 μM, and 1.4 ± 0.17 μM, respectively). With several of these pharmacophores already possessing blood–brain barrier (BBB) permeability properties, or are predicted to penetrate the BBB, these hits present novel starting points for optimization as future treatments for pFLA-caused diseases

Evaluation of a class of isatinoids identified from a high-throughput screen of human kinase inhibitors as anti-Sleeping Sickness agents

New treatments are needed for neglected tropical diseases (NTDs) such as Human African trypanosomiasis (HAT), Chagas disease, and schistosomiasis. Through a whole organism high-throughput screening campaign, we previously identified 797 human kinase inhibitors that grouped into 59 structural clusters and showed activity against T. brucei, the causative agent of HAT. We herein report the results of further investigation of one of these clusters consisting of substituted isatin derivatives, focusing on establishing structure-activity and -property relationship scope. We also describe their in vitro absorption, distribution, metabolism, and excretion (ADME) properties. For one isatin, NEU-4391, which offered the best activity-property profile, pharmacokinetic parameters were measured in mice

<i>Trypanosoma brucei</i> DHRF-TS revisited:characterisation of a bifunctional and highly unstable recombinant dihydrofolate reductase-thymidylate synthase

<div><p>Bifunctional dihydrofolate reductase–thymidylate synthase (DHFR-TS) is a chemically and genetically validated target in African trypanosomes, causative agents of sleeping sickness in humans and nagana in cattle. Here we report the kinetic properties and sensitivity of recombinant enzyme to a range of lipophilic and classical antifolate drugs. The purified recombinant enzyme, expressed as a fusion protein with elongation factor Ts (Tsf) in ThyA^- <i>Escherichia coli</i>, retains DHFR activity, but lacks any TS activity. TS activity was found to be extremely unstable (half-life of 28 s) following desalting of clarified bacterial lysates to remove small molecules. Stability could be improved 700-fold by inclusion of dUMP, but not by other pyrimidine or purine (deoxy)-nucleosides or nucleotides. Inclusion of dUMP during purification proved insufficient to prevent inactivation during the purification procedure. Methotrexate and trimetrexate were the most potent inhibitors of DHFR (<i>K</i>_i 0.1 and 0.6 nM, respectively) and FdUMP and nolatrexed of TS (<i>K</i>_i 14 and 39 nM, respectively). All inhibitors showed a marked drop-off in potency of 100- to 1,000-fold against trypanosomes grown in low folate medium lacking thymidine. The most potent inhibitors possessed a terminal glutamate moiety suggesting that transport or subsequent retention by polyglutamylation was important for biological activity. Supplementation of culture medium with folate markedly antagonised the potency of these folate-like inhibitors, as did thymidine in the case of the TS inhibitors raltitrexed and pemetrexed.</p></div

Gene Expression Profiling and Molecular Characterization of Antimony Resistance in Leishmania amazonensis

Leishmania are unicellular microorganisms that can be transmitted to humans by the bite of sandflies. They cause a spectrum of diseases called leishmaniasis, which are classified as neglected tropical diseases by the World Health Organization. The treatment of leishmaniasis is based on the administration of antimony-containing drugs. These drugs have been used since 1947 and still constitute the mainstay for leishmaniasis treatment in several countries. One of the problems with these compounds is the emergence of resistance. Our work seeks to understand how these parasites become resistant to the drug. We studied antimony-resistant Leishmania amazonensis mutants. We analyzed gene expression at the whole genome level in antimony-resistant parasites and identified mechanisms used by Leishmania for resistance. This work could help us in developing new strategies for treatment in endemic countries where people are unresponsive to antimony-based chemotherapy. The identification of common mechanisms among different species of resistant parasites may also contribute to the development of diagnostic kits to identify and monitor the spread of resistance

Molecular mechanism of drug resistance in parasites

El mecanismo de resistencia a fármacos es un proceso multifactorial, en el que pueden coexistir varios mecanismos, entre ellos: modificaciones en la entrada del fármaco, inactivación del fármaco, amplificación de genes que codifican para las proteínas blanco de acción o proteínas implicadas en la eliminación del fármaco al exterior celular, mutaciones en la proteína blanco de acción, y reparación del daño celular. En los últimos años, nuestro grupo ha estudiado sobre los protozoos parásitos Leishmania (L. tropica y L. infantum ) y Trypanosoma cruzi, algunos de estos mecanismos, con especial interés en las proteínas transportadoras pertenecientes a la superfamilia ABC (ATP-hinding kasette), conocidas como Glicoproteínas-P, implicadas en la eliminación de fármacos y sustancias tóxicas. El estudio molecular y funcional de estos mecanismos, facilitará el desarrollo de estrategias alternativas de tratamiento a emplear en casos de resistencia a fármacos en parásitos.Drug resistance is a multifactorial process involving different coexistent mechanisms, among them: modifications of drug entry, intracellular inactivation of drug, amplification of genes coding for target proteins or proteins involved in drug efflux, mutations in target proteins and increased repair of cell damage. Last years, our research group has been involved in the study of drug resistant mechanisms in the protozoan parasites Leishmania (L. tropica y L. infantum) and Trypanosoma cruzi. Our focus has been related with the study of transporters inc1uded in the superfamily ABC (ATP-binding cassette), specifically the P-glycoproteins involved in efflux of drugs and xenobiotics. Molecular and functional studies of these mechanisms, will help significantly the development of treatment alternative strategies to use in case of drug resistance in parasites

Mecanismo molecular de resistencia a fármacos en parásitos

El mecanismo de resistencia a fármacos es un proceso multifactorial, en el que pueden coexistir varios mecanismos, entre ellos: modificaciones en la entrada del fármaco, inactivación del fármaco, amplificación de genes que codifican para las proteínas blanco de acción o proteínas implicadas en la eliminación del fármaco al exterior celular, mutaciones en la proteína blanco de acción, y reparación del daño celular. En los últimos años, nuestro grupo ha estudiado sobre los protozoos parásitos Leishmania (L. tropica y L. infantum ) y Trypanosoma cruzi, algunos de estos mecanismos, con especial interés en las proteínas transportadoras pertenecientes a la superfamilia ABC (ATP-hinding kasette), conocidas como Glicoproteínas-P, implicadas en la eliminación de fármacos y sustancias tóxicas. El estudio molecular y funcional de estos mecanismos, facilitará el desarrollo de estrategias alternativas de tratamiento a emplear en casos de resistencia a fármacos en parásitos.Drug resistance is a multifactorial process involving different coexistent mechanisms, among them: modifications of drug entry, intracellular inactivation of drug, amplification of genes coding for target proteins or proteins involved in drug efflux, mutations in target proteins and increased repair of cell damage. Last years, our research group has been involved in the study of drug resistant mechanisms in the protozoan parasites Leishmania (L. tropica y L. infantum) and Trypanosoma cruzi. Our focus has been related with the study of transporters inc1uded in the superfamily ABC (ATP-binding cassette), specifically the P-glycoproteins involved in efflux of drugs and xenobiotics. Molecular and functional studies of these mechanisms, will help significantly the development of treatment alternative strategies to use in case of drug resistance in parasites