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1.
PLoS One ; 16(7): e0254498, 2021.
Article in English | MEDLINE | ID: covidwho-1325435

ABSTRACT

To screen for additional vaccine candidate antigens of Plasmodium pre-erythrocytic stages, fourteen P. falciparum proteins were selected based on expression in sporozoites or their role in establishment of hepatocyte infection. For preclinical evaluation of immunogenicity of these proteins in mice, chimeric P. berghei sporozoites were created that express the P. falciparum proteins in sporozoites as an additional copy gene under control of the uis4 gene promoter. All fourteen chimeric parasites produced sporozoites but sporozoites of eight lines failed to establish a liver infection, indicating a negative impact of these P. falciparum proteins on sporozoite infectivity. Immunogenicity of the other six proteins (SPELD, ETRAMP10.3, SIAP2, SPATR, HT, RPL3) was analyzed by immunization of inbred BALB/c and outbred CD-1 mice with viral-vectored (ChAd63 or ChAdOx1, MVA) vaccines, followed by challenge with chimeric sporozoites. Protective immunogenicity was determined by analyzing parasite liver load and prepatent period of blood stage infection after challenge. Of the six proteins only SPELD immunized mice showed partial protection. We discuss both the low protective immunogenicity of these proteins in the chimeric rodent malaria challenge model and the negative effect on P. berghei sporozoite infectivity of several P. falciparum proteins expressed in the chimeric sporozoites.


Subject(s)
Malaria, Falciparum/parasitology , Plasmodium falciparum/pathogenicity , Animals , Antibodies, Protozoan/immunology , Antibodies, Protozoan/metabolism , Antigens, Protozoan/immunology , Antigens, Protozoan/metabolism , Erythrocytes/metabolism , Female , Malaria Vaccines/therapeutic use , Malaria, Falciparum/genetics , Malaria, Falciparum/immunology , Mice , Mice, Inbred BALB C , Plasmodium falciparum/metabolism , Protozoan Proteins/metabolism , Sporozoites/pathogenicity
2.
Molecules ; 26(8)2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1302425

ABSTRACT

Malaria is one of the most life-threatening infectious diseases and constitutes a major health problem, especially in Africa. Although artemisinin combination therapies remain efficacious to treat malaria, the emergence of resistant parasites emphasizes the urgent need of new alternative chemotherapies. One strategy is the repurposing of existing drugs. Herein, we reviewed the antimalarial effects of marketed antibiotics, and described in detail the fast-acting antibiotics that showed activity in nanomolar concentrations. Antibiotics have been used for prophylaxis and treatment of malaria for many years and are of particular interest because they might exert a different mode of action than current antimalarials, and can be used simultaneously to treat concomitant bacterial infections.


Subject(s)
Antimalarials/therapeutic use , Drug Repositioning/methods , Animals , Anti-Bacterial Agents/therapeutic use , Drug Resistance/genetics , Humans , Malaria/physiopathology , Plasmodium falciparum/genetics , Plasmodium falciparum/pathogenicity
3.
Int J Mol Sci ; 22(11)2021 May 28.
Article in English | MEDLINE | ID: covidwho-1256561

ABSTRACT

Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite Plasmodium falciparum, aspartyl proteases of P. falciparum (plasmepsins) and the Sars-CoV-2 viral proteases. Despite some unfulfilled expectations over previous decades, the three reviewed targets clearly demonstrate that selective protease inhibitors provide effective therapeutic solutions for the two most impacting infectious diseases nowadays-malaria and COVID-19.


Subject(s)
COVID-19/drug therapy , Drug Development/methods , Malaria/drug therapy , Plasmodium falciparum/drug effects , Protease Inhibitors/pharmacology , Proteasome Endopeptidase Complex/drug effects , SARS-CoV-2/drug effects , Aspartic Acid Endopeptidases/metabolism , COVID-19/enzymology , COVID-19/metabolism , Humans , Malaria/enzymology , Malaria/metabolism , Plasmodium falciparum/pathogenicity , SARS-CoV-2/pathogenicity
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