RESUMO
Sialoadhesin (Sn) is a surface receptor expressed on a subset of macrophages in steady state conditions. During inflammation and diseases, Sn is highly upregulated on macrophages and blood monocytes. Therefore, therapies using monoclonal antibodies (mAbs) to target Sn-positive (Sn+) cells are a potential strategy for targeted treatment. It has been shown that Sn internalizes after binding with a mAb, though it is not clear whether this is species-specific. In this study, new Sn-specific mAbs were developed and analyzed for cross-reactivity between species. In addition, the newly developed mAbs were compared to mAbs used in previous research for their epitope recognition and other Sn-specific characteristics. Both species-specific and cross-reactive antibodies could be identified. Furthermore, sialic acid-binding of red blood cells (RBC) could be inhibited with mAbs recognizing different epitopes and all mAb showed internalization of Sn. The newly developed mAbs can be used as novel tools for Sn research and further analysis of Sn internalization in different species.
RESUMO
Visceral leishmaniasis is a severe parasitic disease that is one of the most neglected tropical diseases. Treatment options are limited, and there is an urgent need for new therapeutic agents. Following an HTS campaign and hit optimization, a novel series of amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series.
Assuntos
Antiparasitários/química , Leishmania donovani/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Pirazóis/química , Ureia/análogos & derivados , Ureia/química , Animais , Antiparasitários/farmacocinética , Antiparasitários/farmacologia , Cricetinae , Feminino , Humanos , Leishmaniose Visceral/tratamento farmacológico , Mesocricetus , Microssomos/metabolismo , Pirazóis/farmacocinética , Pirazóis/farmacologia , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
Although Aspergillus infections pose a growing threat to immunocompromised individuals, the limited range of existing drugs does not allow efficient management of invasive aspergillosis. Moreover, drug resistance is becoming increasingly common. Given that drug discovery relies on high-quality animal studies, careful design of in vivo models for invasive aspergillosis could facilitate the identification of novel antifungals. In this review, we discuss key aspects of animal models for invasive aspergillosis, covering laboratory animal species, immune modulation, inoculation routes, Aspergillus strains, treatment strategies and efficacy assessment, to enable the reader to tailor specific protocols for different types of preclinical antifungal evaluation study.
Assuntos
Antifúngicos/farmacologia , Aspergilose/tratamento farmacológico , Modelos Animais de Doenças , Animais , Aspergilose/microbiologia , Aspergillus/efeitos dos fármacos , Aspergillus/isolamento & purificação , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Farmacorresistência Fúngica , HumanosRESUMO
On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile resulting from the extension into the P2' pocket of the HIV-1 protease.