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Projeto de investigação
A “Click and CO Release” approach for the targeted delivery of therapeutic CO in vivo
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Site-selective installation of BASHY fluorescent dyes to Annexin V for targeted detection of apoptotic cells
Publication . Cal, Pedro M.S.D.; Sieglitz, Florian; Santos, Fábio; Parente Carvalho, Cátia; Guerreiro, Ana; Bertoldo, Jean B.; Pischel, Uwe; Gois, Pedro M. P.; Bernardes, Gonçalo J. L.
Fluorophores are indispensable for imaging biological processes. We report the design and synthesis of azide-tagged boronic acid salicylidenehydrazone (BASHY) dyes and their use for site-selective labelling of Annexin V. The Annexin V-BASHY conjugate maintained function and fluorescence as demonstrated by the targeted detection of apoptotic cells.
Unveiling Englerin A as a modulator of L-type calcium channels
Publication . Rodrigues, Tiago; Sieglitz, Florian; Somovilla, Víctor J.; Cal, Pedro M.S.D.; Galione, Antony; Corzana, Francisco; Bernardes, Gonçalo J. L.
The voltage-dependent L-type Ca(2+) channel was identified as a macromolecular target for (-)-englerin A. This finding was reached by using an unprecedented ligand-based prediction platform and the natural product piperlongumine as a pharmacophore probe. (-)-Englerin A features high substructure dissimilarity to known ligands for voltage-dependent Ca(2+) channels, selective binding affinity for the dihydropyridine site, and potent modulation of calcium signaling in muscle cells and vascular tissue. The observed activity was rationalized at the atomic level by molecular dynamics simulations. Experimental confirmation of this hitherto unknown macromolecular target expands the bioactivity space for this natural product and corroborates the effectiveness of chemocentric computational methods for prioritizing target-based screens and identifying binding counterparts of complex natural products.
Brain-sparing sympathofacilitators mitigate obesity without adverse cardiovascular effects
Publication . Mahú, Inês; Barateiro, Andreia; Rial-Pensado, Eva; Martinéz-Sánchez, Noelia; Vaz, Sandra H.; Cal, Pedro M.S.D.; Jenkins, Benjamin; Rodrigues, Tiago M.; Cordeiro, Carlos; Costa, Miguel F.; Mendes, Raquel; Seixas, Elsa; Pereira, Mafalda M.A.; Kubasova, Nadiya; Gres, Vitka; Morris, Imogen; Temporão, Carolina; Olivares, Marta; Sanz, Yolanda; Koulman, Albert; Corzana, Francisco; Sebastião, Ana M; López, Miguel; Bernardes, Gonçalo J. L.; Domingos, Ana I.
Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
OE
Número da atribuição
SFRH/BPD/103172/2014