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1.
Reprod Toxicol ; 89: 107-114, 2019 10.
Article in English | MEDLINE | ID: mdl-31310803

ABSTRACT

Malaria in pregnant women is associated with risk of maternal and perinatal morbidity and mortality, and there are few antimalarial drugs considered safe to treat them, so it is necessary to develop safer antimalarial medicines. The goal of this study was to develop an animal model for human malaria during pregnancy by characterizing the maternal and fetal outcomes in malaria infected Swiss mice. For that, in the present study, we evaluated the outcome of pregnancy in Swiss mice infected with Plasmodium berghei ANKAGFP. We observed a reduction of fetal body weight and signs of skeletal ossification retardation in the offspring of mice infected on GD 12. The group of mice infected with malaria presented premature deliveries and histopathology changes consistent with placental malaria. Our study suggests that Swiss Webster mice infected with P. berghei ANKAGFP on GD 12 might be a valuable model to investigate the safety and the efficacy of new antimalarial drugs indicated to pregnant women.


Subject(s)
Antimalarials/therapeutic use , Fetal Development/drug effects , Fetal Growth Retardation/prevention & control , Malaria/drug therapy , Plasmodium berghei/drug effects , Pregnancy Complications, Parasitic/drug therapy , Animals , Animals, Newborn , Antimalarials/administration & dosage , Disease Models, Animal , Female , Fetal Growth Retardation/parasitology , Gestational Age , Malaria/parasitology , Plasmodium berghei/growth & development , Pregnancy , Pregnancy Complications, Parasitic/parasitology , Pregnancy Outcome
2.
J Interferon Cytokine Res ; 36(3): 180-91, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26700737

ABSTRACT

Type I interferons (IFNs) exhibit broad-spectrum antiviral activity, with potential utility against emerging acute virus infections that pose a threat to global health. Recombinant IFN-αs that have been approved for clinical use require cold storage and are administered through intramuscular or subcutaneous injection, features that are problematic for global distribution, storage, and administration. Cognizant that the biological potency of an IFN-α subtype is determined by its binding affinity to the type I IFN receptor, IFNAR, we identified a panel of small molecule nonpeptide compounds using an in silico screening strategy that incorporated specific structural features of amino acids in the receptor-binding domains of the most potent IFN-α, IFN alfacon-1. Hit compounds were selected based on ease of synthesis and formulation properties. In preliminary biological assays, we provide evidence that these compounds exhibit antiviral activity. This proof-of-concept study validates the strategy of in silico design and development for IFN mimetics.


Subject(s)
Antiviral Agents/pharmacology , Encephalomyocarditis virus/drug effects , Interferon-alpha/chemistry , Peptidomimetics/pharmacology , Receptor, Interferon alpha-beta/agonists , Small Molecule Libraries/pharmacology , Antiviral Agents/chemical synthesis , B-Lymphocytes/drug effects , B-Lymphocytes/pathology , B-Lymphocytes/virology , Cell Line, Tumor , Computer Simulation , Drug Design , Encephalomyocarditis virus/growth & development , Gene Expression , High-Throughput Screening Assays , Humans , Ligands , Models, Molecular , Peptidomimetics/chemical synthesis , Protein Structure, Secondary , Receptor, Interferon alpha-beta/chemistry , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , Recombinant Proteins/chemistry , Small Molecule Libraries/chemical synthesis , Structure-Activity Relationship , User-Computer Interface
3.
Bioorg Med Chem ; 22(9): 2739-52, 2014 May 01.
Article in English | MEDLINE | ID: mdl-24685704

ABSTRACT

Idiopathic or immune thrombocytopenia (ITP) is a serious clinical disorder involving the destruction of platelets by macrophages. Small molecule therapeutics are highly sought after to ease the burden on current therapies derived from human sources. Earlier, we discovered that dimers of five-membered heterocycles exhibited potential to inhibit phagocytosis of human RBCs by macrophages. Here, we reveal a structure-activity relationship of the bis-pyrazole class of molecules with -C-C-, -C-N- and -C-O- linkers, and their evaluation as inhibitors of phagocytosis of antibody-opsonized human RBCs as potential therapeutics for ITP. We have uncovered three potential candidates, 37, 47 and 50, all carrying a different linker connecting the two pyrazole moieties. Among these compounds, hydroxypyrazole derivative 50 is the most potent compound with an IC50 of 14 ± 9 µM for inhibiting the phagocytosis of antibody-opsonized human RBCs by macrophages. None of the compounds exhibited significant potential to induce apoptosis in peripheral blood mononuclear cells (PBMCs). Current study has revealed specific functional features, such as up to 2-atom spacer arm and alkyl substitution at one of the N(1) positions of the bivalent pyrazole core to be important for the inhibitory activity.


Subject(s)
Pyrazoles/chemistry , Antibodies/immunology , Erythrocytes/cytology , Erythrocytes/drug effects , Humans , Leukocytes, Mononuclear/immunology , Phagocytosis/drug effects , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombocytopenic, Idiopathic/immunology , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Structure-Activity Relationship
4.
Bioorg Med Chem ; 22(3): 978-85, 2014 Feb 01.
Article in English | MEDLINE | ID: mdl-24433965

ABSTRACT

Small molecules that mimic IFN-α epitopes that interact with the cell surface receptor, IFNAR, would be useful therapeutics. One such 8-amino acid region in IFN-α2, designated IRRP-1, was used to derive 11 chemical compounds that belong to 5 distinct chemotypes, containing the molecular features represented by the key residues Leu30, Arg33, and Asp35 in IRRP-1. Three of these compounds exhibited potential mimicry to IRRP-1 and, in cell based assays, as predicted, effectively inhibited IFNAR activation by IFN-α. Of these, compound 3 did not display cell toxicity and reduced IFN-α-inducible STAT1 phosphorylation and STAT-DNA binding. Based on physicochemical properties' analyses, our data suggest that moieties with acidic pKa on the small molecule may be a necessary element for mimicking the carboxyl group of Asp35 in IRRP-1. Our data confirm the relevance of this strategy of molecular mimicry of ligand-receptor interaction domains of protein partners for small molecule drug discovery.


Subject(s)
Epitopes/chemistry , Receptor, Interferon alpha-beta/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Aspartic Acid/chemistry , Cell Line/drug effects , Drug Evaluation, Preclinical/methods , Epitopes/metabolism , Humans , Interferon-alpha/metabolism , Models, Molecular , Molecular Mimicry , Peptides/chemistry , Phosphorylation/drug effects , Protein Conformation , Protein Structure, Tertiary , Receptor, Interferon alpha-beta/chemistry , STAT1 Transcription Factor/metabolism
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