The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins

E6 viral oncoproteins are key players in epithelial tumors induced by papillomaviruses in vertebrates, including cervical cancer in humans. E6 proteins target many host proteins by specifically interacting with acidic LxxLL motifs. We solved the crystal structures of bovine (BPV1) and human (HPV16) papillomavirus E6 proteins bound to LxxLL peptides from the focal adhesion protein paxillin and the ubiquitin ligase E6AP, respectively. In both E6 proteins, two zinc domains and a linker helix form a basic-hydrophobic pocket, which captures helical LxxLL motifs in a way compatible with other interaction modes. Mutational inactivation of the LxxLL binding pocket disrupts the oncogenic activities of both E6 proteins. This work reveals the structural basis of both the multifunctionality and the oncogenicity of E6 proteins

Determination de la preference diastereofaciale de l'addition 1-4 d'organocuprates sur des cetones lineaires alpha-beta insaturees conjuguees, gamma-delta diastereoselectivement disubstitues. - Etude de la reaction de metalla-Claisen en serie allenique. Applications a diverses carbocyclisations

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : TD 79310 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Conjugate addition of organocuprates on γ-methyl-δ-oxy-α,β-enones. Influence of the alkoxy substituent on the diastereoselection

The stereochemistry of the conjugate addition of cuprates to the title compounds is mainly governed by the ?-methyl group, but the alkoxy substituent also plays a role. A ?-methyl group exerts the dominant effect in the conjugate addition of a cuprate on a ?-methyl-d-oxy-a,ß-enone, leading to pure anti-addition to the syn substrate, whereas for the anti substrate, a chelating group on oxygen (MEM) definitely assists anti addition. The syn enone reacts exclusively according to the Morokuma model, whereas the anti enone exhibits a chelate effect and fits better with the Isobe model. In both cases, capture of the enolate by iodomethane is stereoselective, so that four contiguous substituted carbons can be created from the initial two, with good stereoselectivity

Activity in vivo of anti-Trypanosoma cruzi compounds selected from a high throughput screening.

Novel technologies that include recombinant pathogens and rapid detection methods are contributing to the development of drugs for neglected diseases. Recently, the results from the first high throughput screening (HTS) to test compounds for activity against Trypanosoma cruzi trypomastigote infection of host cells were reported. We have selected 23 compounds from the hits of this HTS, which were reported to have high anti-trypanosomal activity and low toxicity to host cells. These compounds were highly purified and their structures confirmed by HPLC/mass spectrometry. The compounds were tested in vitro, where about half of them confirmed the anti-T. cruzi activity reported in the HTS, with IC50 values lower than 5 µM. We have also adapted a rapid assay to test anti-T. cruzi compounds in vivo using mice infected with transgenic T. cruzi expressing luciferase as a model for acute infection. The compounds that were active in vitro were also tested in vivo using this assay, where we found two related compounds with a similar structure and low in vitro IC50 values (0.11 and 0.07 µM) that reduce T. cruzi infection in the mouse model more than 90% after five days of treatment. Our findings evidence the benefits of novel technologies, such as HTS, for the drug discovery pathway of neglected diseases, but also caution about the need to confirm the results in vitro. We also show how rapid methods of in vivo screening based in luciferase-expressing parasites can be very useful to prioritize compounds early in the chain of development

Zika antiviral chemotherapy: identification of drugs and promising starting points for drug discovery from an FDA-approved library

Submitted by Adagilson Silva ([email protected]) on 2017-05-11T17:39:14Z No. of bitstreams: 1 27909576 2016 pas-zik.pdf: 4873876 bytes, checksum: 69eb4a73b3e93bb76910afeeda15c7a7 (MD5)Approved for entry into archive by Adagilson Silva ([email protected]) on 2017-05-11T17:39:32Z (GMT) No. of bitstreams: 1 27909576 2016 pas-zik.pdf: 4873876 bytes, checksum: 69eb4a73b3e93bb76910afeeda15c7a7 (MD5)Made available in DSpace on 2017-05-11T17:39:32Z (GMT). No. of bitstreams: 1 27909576 2016 pas-zik.pdf: 4873876 bytes, checksum: 69eb4a73b3e93bb76910afeeda15c7a7 (MD5) Previous issue date: 2016Centro Nacional de Pesquisa em Energia e Materiais. Laboratório Nacional de Biociências. Campinas, SP, Brazil / Instituto Butantan. São Paulo, SP, Brazil.BIOASTER. Paris, France.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Recife, PE, Brasil.Centro Nacional de Pesquisa em Energia e Materiais. Laboratório Nacional de Biociências. Campinas, SP, Brazil / Instituto Butantan. São Paulo, SP, Brazil.Background The recent epidemics of Zika virus (ZIKV) implicated it as the cause of serious and potentially lethal congenital conditions such microcephaly and other central nervous system defects, as well as the development of the Guillain-Barré syndrome in otherwise healthy patients. Recent findings showed that anti-Dengue antibodies are capable of amplifying ZIKV infection by a mechanism similar to antibody-dependent enhancement, increasing the severity of the disease. This scenario becomes potentially catastrophic when the global burden of Dengue and the advent of the newly approved anti-Dengue vaccines in the near future are taken into account. Thus, antiviral chemotherapy should be pursued as a priority strategy to control the spread of the virus and prevent the complications associated with Zika. Methods Here we describe a fast and reliable cell-based, high-content screening assay for discovery of anti-ZIKV compounds. This methodology has been used to screen the National Institute of Health Clinical Collection compound library, a small collection of FDA-approved drugs. Results and conclusion From 725 FDA-approved compounds triaged, 29 (4%) were found to have anti-Zika virus activity, of which 22 had confirmed (76% of confirmation) by dose-response curves. Five candidates presented selective activity against ZIKV infection and replication in a human cell line. These hits have abroad spectrum of chemotypes and therapeutic uses, offering valuable opportunities for selection of leads for antiviral drug discovery

Looking for Solutions to the Pitfalls of Developing Novel Antibacterials in an Economically Challenging System

The increase in antibacterial resistance (ABR) currently equates in the minds of many with the distant fear that certain antibiotics will not work in 30 years on certain bacteria found in places the majority of us never go to. However, in reality, rising ABR already seriously threatens the effectiveness of compounds with which we treat common bacterial infections, which means that ABR is currently and will continue to undermine the foundations of modern medicine, including surgery and cancer treatment in hospitals, cities and countries across the world. That is why ABR is widely considered a global threat and one of the biggest problems of our current civilization. Conversely, antibiotic developments to market are few. Therefore, in this paper, we have illustrated the barriers to antimicrobial R&D the following questions and provided solutions to effective antimicrobial R&D

Test for activity <i>in vivo</i> of compounds active <i>in vitro</i>.

<p>Groups of five mice were infected with <i>T. cruzi</i> and treated with different compounds following the protocol shown in (A). (B) Quantification of parasite infection levels in the groups of mice treated with the different compounds is expressed as <i>T. cruzi</i> index. Compounds are identified by their CID. Results are expressed as average ± standard deviation (*, <i>P</i><0.05). (C) One representative mouse of each group treated with compounds CID-12402750 and CID-24892493.</p

Compound CID-12402750 shows trypanostatic activity <i>in vitro</i>.

<p>NIH-3T3 fibroblasts were incubated with <i>T. cruzi</i> trypomastigotes for 2 h before washing of extracellular <i>T. cruzi</i> and addition of drugs. Cells were incubated for 3 days, stained with an anti-<i>T. cruzi</i> antibody and DAPI to visualize DNA. Control infection (A) or infection in the presence of compound CID-12402750 at IC5 (B) and IC100 (C) concentration. These are representative images from a total of 50 fields observed in each condition. Scale bar: 10 µm.</p