The Biomembranes Unit is mainly focused on the biochemical and biophysical processes occurring at membrane level of human cells, as well as of their viral and bacterial pathogens.
We have been working on the study of the two steps of the life cycle of enveloped viruses (mainly HIV-1 and dengue virus) that involve biomembranes: the entrance of the virus or its content into the target cell and the assembly of new virions. Our studies have clarified the mechanism of action at the molecular level of some HIV entry inhibitors and pointed out strategies to improve their efficacy. Regarding dengue virus (DENV), our recent studies demonstrated that the DENV capsid (C) protein binds to proteins on the surface of intracellular lipid droplets (LD), majorly perilipin 3 (TIP47). This interaction, essential to viral replication, depends on the high intracellular potassium concentration, and may regulate the availability of the C protein, allowing its proper participation on the virus replication cycle. We have also showed that a peptide designed based on a conserved segment within the disordered N-terminal region of DENV C region is able to inhibit the DENV C – LD binding. These advances pave the way to drug development approaches, in which inhibitory efficiency may be improved through lead optimization.
We have also been studying the binding of fibrinogen to the erythrocyte membrane and its relevance as a significant cardiovascular risk factor. At this level, we have identified a previously unknown receptor for fibrinogen on the erythrocyte membrane, which is altered in some human pathologies. Furthermore, we identified strategies to inhibit its contribution to the erythrocyte hyperaggregation associated with high plasma fibrinogen levels.
The Biomembranes Unit is also involved on the pre-clinical evaluation of the membrane activity and mechanism of action at the molecular level of antimicrobial peptides (AMP) and cell-penetrating peptides (CPP), most of them based on naturally occurring amino acid sequences.
On the Nanotechnology/Nanomedicine area, we are also working on the development of innovative biosensor systems, with improved selectivity and sensitivity (e.g., nanoparticles and amyloid-based biosensors).
Based on the results obtained so far, the work to be developed by the Biomembranes Unit on the near future may contribute for the identification of new drug targets, therapeutic strategies and/or diagnostic methods for important human pathologies, such as cardiovascular diseases, HIV/AIDS and dengue.
Ongoing Research Projects
An atomic force microscopy facility devoted to biomedical and
biochemical studies at the molecular-level. Coordinator: M. Castanho
(FCT - REEQ/140/BIO/2005)
2007/10 Identificação de um marcador de
interacção eficaz na terapêutica da doença de Alzheimer. Coordinator: S.
Gonçalves (Merck Sharp & Dohme Foundation)
2007/11 Fibrinogen-dependent signalling
in microvascular blood cell function – implications of inflammation and
cardiovascular disease. Coordinator: C. Saldanha. FCT -
2007/10 The role of lipid membranes in the dengue virus cell infection. Coordinator: M. Castanho. FCT - PTDC/QUI/69937/2006.
Metal- and magnetic nanoparticles functionalized with biological
molecules: towards bio-nanoprobes. Coordinator: E. Pereira. FCT -
Interacção da proteína capsídica do vírus da dengue com membranas e
corpúsculos lipídicos – Relevância para a patogénese viral. Coordinator:
N.C. Santos. FCT-CAPES Project.
2010/13 Cell membrane features in HIV entry and its inhibition. Coordinator: N.C. Santos. FCT - PTDC/QUI-BIQ/104787/2008.
Inherent antibacterial activity in peptide-based hydrogels for tissue
regeneration. Coordinator: A.S. Veiga. FCT - PTDC/SAU-BEB/099142/2008.
MEMPEPACROSS: Membrane-active peptides across disciplines and
continents: An integrated approach to find new strategies to fight
bacteria, dengue virus and neurodegeneration. Coordinator: N.C. Santos.
Programme “People” – Marie Curie International Research Staff Exchange
Scheme – Call identifier: FP7-PEOPLE-2009-IRSES. Coordinator: N.C.
force microscopy-based molecular recognition of fibrinogen receptors in
platelets and erythrocytes. Applications in health and disease.
Coordinator: N.C. Santos. Calouste Gulbenkian Foundation.
The interplay between lipid droplets, RNA and the capsid protein during
dengue virus assembly and encapsidation. Coordinator: I.C. Martins.
Calouste Gulbenkian Foundation.
LIPIDENGUE: The role of hepatic lipid membranes and lipid droplets in
Dengue virus encapsidation. A gateway to new therapies. Coordinator: M.
Castanho. FCT - PTDC/QUI-BIQ/112929/2009.
FCT VIH/SAU/0047/2011, "Multi-target HIV entry inhibitors delivery by cationic liposomes". Coordinator: Salomé Veiga.
Johnson Mak (Melbourne, Australia)
Marcel Tabak (Sao Paulo, Brazil)
Joseph Zasadzinski (Santa Barbara, USA)
Simon Connell (Leeds, UK)
Andrea Da Poian (Rio de Janeiro, Brazil)
Anne Ulrich (Karlsruhe, Germany)
Gregory Melikian (Atlanta, USA)
Benhur Lee (Los Angeles, USA)
Gang Liu (Beijing, P.R. China)
Roche (Palo Alto, USA)
Xoma Corporation (Berkley, USA)
2010 Research Programme in Frontiers of Life Sciences from Calouste Gulbenkian Foundation (Ivo Martins).
2009 Gulbenkian Prize to Stimulus for Research 2009 (Marco M. Domingues).
2005 José Luís Champalimaud Prize on HIV Research (Applied Research and Technologies area).
2004 José Luís Champalimaud Prize on HIV Research (Basic Research area).
2001 Calouste Gulbenkian Foundation Prize (for researchers under 31).
Erythrocytes labeled with the membrane potential probe Di-8-ANEPPS
Structures of the membrane potential probe di-8-ANEPPS,
incorporated in a phosphatidylcholine membrane leaflet
Lipid rafts model
HIV lipid composition
Coated gold nanoparticles conjugation with proteins
Erythrocytes imaging by atomic force microscopy (AFM)
Platelet imaging by atomic force microscopy (AFM)