Enabling strategies for enhanced whole-sporozoite malaria vaccines

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Elimination of hepatic rodent plasmodium parasites by amino acid supplementation

Publication . Meireles, Patricia; Brás, Daniela; Fontinha, Diana; Chora, Ângelo Ferreira; Serre, Karine; Mendes, António M.; Prudêncio, Miguel

Plasmodium parasites, causative agents of malaria, scavenge host nutrients to sustain their intracellular replication. Modulation of the host's nutritional status can potentially help control infection by limiting the parasite's access to nutrients, or by boosting the immune system. Here, we show that dietary supplementation of mice employing a combination of arginine (R) with two additional amino acids, lysine (K) and valine (V), termed RKV, significantly decreases Plasmodium liver infection. RKV supplementation results in the elimination of parasites at a late stage of their development in the liver. Our data employing genetic knockout mouse models and in vivo depletion of specific cell populations suggest that RKV supplementation boosts the host's overall innate immune response, and that parasite elimination is dependent on MyD88 signaling in immune cells. The immunostimulatory effect of RKV supplementation opens a potential role for dietary supplementation as an adjuvant for prophylaxis or immunization strategies against Plasmodium infection.

2020Journal article

Open access

4,9‐Diaminoacridines and 4‐Aminoacridines as dual‐stage antiplasmodial hits

Publication . Fonte, Mélanie; Tassi, Natália; Fontinha, Diana; Bouzón‐Arnáiz, Inés; Ferraz, Ricardo; Araújo, Maria J.; Fernàndez‐Busquets, Xavier; Prudêncio, Miguel; Gomes, Paula; Teixeira, Cátia

Multi-stage drugs have been prioritized in antimalarial drug discovery, as targeting more than one process in the Plasmodium life cycle is likely to increase efficiency, while decreasing the chances of emergence of resistance by the parasite. Herein, we disclose two novel acridine-based families of compounds that combine the structural features of primaquine and chloroquine. Compounds prepared and studied thus far retained the in vitro activity displayed by the parent drugs against the erythrocytic stages of chloroquine-sensitive and -resistant Plasmodium falciparum strains, and against the hepatic stages of Plasmodium berghei, hence acting as dual-stage antiplasmodial hits.

2020Journal article

Restricted access

Synthesis and structure-activity relationships of new chiral spiro-ß-lactams highly active against HIV-1 and Plasmodium

Publication . G. Alves, Nuno; Bártolo, Inês; Alves, Américo; Fontinha, Diana; Francisco, Denise; Lopes, Susana M. M.; Soares, Maria I. L.; Simões, Carlos J. V.; Prudêncio, Miguel; Taveira, Nuno; Melo, Teresa M. V. D. Pinho E

The synthesis and antimicrobial activity of new spiro-β-lactams is reported. The design of the new molecules was based on the structural modulation of two previously identified lead spiro-penicillanates with dual activity against HIV and Plasmodium. The spiro-β-lactams synthesized were assayed for their in vitro activity against HIV-1, providing relevant structure-activity relationship information. Among the tested compounds, two spirocyclopentenyl-β-lactams were identified as having remarkable nanomolar activity against HIV-1. Additionally, the same molecules showed promising antiplasmodial activity, inhibiting both the hepatic and blood stages of Plasmodium infection.

2021Journal article

Restricted access

Unveiling a family of spiro-ß-lactams with anti-HIV and antiplasmodial activity via phosphine-catalyzed [3+2] annulation of 6-alkylidene-penicillanates and allenoates

Publication . Alves, Américo; Alves, Nuno G.; Bártolo, Inês; Fontinha, Diana; Caetano, Soraia; Prudêncio, Miguel; Taveira, Nuno; Melo, Teresa M. V. D. Pinho E

The molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-β-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC50 lower than 50 nM. These eight compounds also showed nanomolar activity against HIV-2, and six of them displayed micromolar antiplasmodial activity against both the hepatic and the blood stages of infection by malaria parasites, in agreement with the lead molecule’s bioactivity profile. The spirocyclopentene-β-lactams screened also showed low cytotoxicity against TZM-bl and Huh7 human cell lines. Overall, a family of new spirocyclopentene penicillanates with potent activity against HIV and/or Plasmodium was identified. The present structure–activity relationship open avenues for further development of spirocyclopentene-β-lactams as multivalent, highly active broad spectrum antimicrobial agents.

2022-10-07Journal article

Open access