MULTI-TARGET HIV ENTRY INHIBITORS DELIVERY BY CATIONIC LIPOSOMES

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Anti-HIV-1 activity of pepRF1, a proteolysis-resistant CXCR4 antagonist derived from Dengue virus capsid protein

Publication . Cadima Couto, Carla Iris; Tauzin, Alexandra; Freire, João Miguel; Figueira, Tiago N.; Silva, Rúben D. M.; Pérez-Peinado, Clara; Cunha-Santos, Catarina; Bártolo, Inês; Taveira, Nuno; Gano, Lurdes; Correia, João D. G.; Goncalves, Joao; Mammano, Fabrizio; Andreu, David; Castanho, Miguel A. R. B.; Veiga, Ana Salomé

There is an urgent need for the development of new anti-HIV drugs that can complement existing medicines to be used against resistant strains. Here, we report the anti-HIV-1 peptide pepRF1, a human serum-resistant peptide derived from the Dengue virus capsid protein. In vitro, pepRF1 shows a 50% inhibitory concentration of 1.5 nM with a potential therapeutic window higher than 53 000. This peptide is specific for CXCR4-tropic strains, preventing viral entry into target cells by binding to the viral coreceptor CXCR4, acting as an antagonist of this receptor. pepRF1 is more effective than T20, the only peptide-based HIV-1 entry inhibitor approved, and excels in inhibiting a HIV-1 strain resistant to T20. Potentially, pepRF1 can be used alone or in combination with other anti-HIV drugs. Furthermore, one can also envisage its use as a novel therapeutic strategy for other CXCR4-related diseases.

2020Journal article

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Anti-HIV-1 Activity of pepRF1, a Proteolysis-Resistant CXCR4 Antagonist Derived from Dengue Virus Capsid Protein

Publication . Cadima Couto, Carla Iris; Tauzin, Alexandra; Freire, João Miguel; Figueira, Tiago N.; Silva, Rúben; Pérez-Peinado, Clara; Cunha-Santos, Catarina; Bártolo, Inês; Taveira, Nuno; Gano, Lurdes; Correia, João D. G.; Goncalves, Joao; Mammano, Fabrizio; Andreu, David; Castanho, Miguel A. R. B.; Veiga, Ana Salomé

There is an urgent need for the development of new anti-HIV drugs that can complement existing medicines to be used against resistant strains. Here, we report the anti-HIV-1 peptide pepRF1, a human serum-resistant peptide derived from the Dengue virus capsid protein. In vitro, pepRF1 shows a 50% inhibitory concentration of 1.5 nM with a potential therapeutic window higher than 53 000. This peptide is specific for CXCR4-tropic strains, preventing viral entry into target cells by binding to the viral coreceptor CXCR4, acting as an antagonist of this receptor. pepRF1 is more effective than T20, the only peptide-based HIV-1 entry inhibitor approved, and excels in inhibiting a HIV-1 strain resistant to T20. Potentially, pepRF1 can be used alone or in combination with other anti-HIV drugs. Furthermore, one can also envisage its use as a novel therapeutic strategy for other CXCR4-related diseases.

2020-12-15Journal article

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Enfuvirtide-protoporphyrin IX dual-loaded liposomes: in vitro evidence of synergy against HIV-1 entry into cells

Publication . Figueira, Tiago Nascimento; Domingues, Marco; Illien, Françoise; Cadima Couto, Carla Iris; Todorovski, Toni; Andreu, David; Sagan, Sandrine; Castanho, Miguel A. R. B.; Walrant, Astrid; Veiga, Ana Salomé

We have developed a nanocarrier consisting of large unilamellar vesicles (LUVs) for combined delivery of two human immunodeficiency virus type 1 (HIV-1) entry inhibitors, enfuvirtide (ENF) and protoporphyrin IX (PPIX). The intrinsic lipophilicity of ENF and PPIX, a fusion inhibitor and an attachment inhibitor, respectively, leads to their spontaneous incorporation into the lipid bilayer of the LUVs nanocarrier. Both entry inhibitors partition significantly toward LUVs composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and a 9:1 mixture of POPC:1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000] (DPPE-PEG2000), representative of conventional and immune-evasive drug delivery formulations, respectively. These colocalize in the core of lipid membranes. Dual-loaded nanocarriers are monodispersed and retain the size distribution, thermotropic behavior, and surface charge of the unloaded form. Combination of the two entry inhibitors in the nanocarrier resulted in improved synergy against HIV-1 entry compared to combination in free form, strongly when immuneevasive formulations are used. We propose that the improved action of the entry inhibitors when loaded into the nanocarriers results from their slow release at the site of viral entry. Overall, liposomes remain largely unexplored platforms for combination of viral entry inhibitors, with potential for improvement of current antiretroviral therapy drug safety and application. Our work calls for a reappraisal of the potential of entry inhibitor combinations and delivery for clinical use in antiretroviral therapy.

2020Journal article

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