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5 results on '"Joyner, C. J."'

1. A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites

Author

Maher, S. P., primary, Bakowski, M. A., additional, Vantaux, A., additional, Flannery, E. L., additional, Andolina, C., additional, Gupta, M., additional, Antonova-Koch, Y., additional, Argomaniz, M., additional, Cabrera-Mora, M., additional, Campo, B., additional, Chao, A. T., additional, Chatterjee, A. K., additional, Cheng, W. T., additional, Chuenchob, E., additional, Cooper, C. A., additional, Cottier, K., additional, Galinski, M. R., additional, Harupa-Chung, A., additional, Ji, H., additional, Joseph, S. B., additional, Lenz, T., additional, Lonardi, S., additional, Matheson, J., additional, Mikolajczak, S. A., additional, Moeller, T., additional, Orban, A., additional, Padín-Irizarry, V., additional, Pan, K., additional, Péneau, J., additional, Prudhomme, J., additional, Roesch, C., additional, Ruberto, A. A., additional, Sabnis, S. S., additional, Saney, C. L., additional, Sattabongkot, J., additional, Sereshki, S., additional, Suriyakan, S., additional, Ubalee, R., additional, Wang, Y., additional, Wasisakun, P., additional, Yin, J., additional, Popovici, J., additional, McNamara, C. W., additional, Joyner, C. J., additional, Nosten, F., additional, Witkowski, B., additional, Le Roch, K. G., additional, and Kyle, D. E., additional

Published
2024
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2. A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways inPlasmodium vivaxHypnozoites

Author

Maher, S. P., primary, Bakowski, M. A., additional, Vantaux, A., additional, Flannery, E. L., additional, Andolina, C., additional, Gupta, M., additional, Antonova-Koch, Y., additional, Argomaniz, M., additional, Cabrera-Mora, M., additional, Campo, B., additional, Chao, A. T., additional, Chatterjee, A. K., additional, Cheng, W. T., additional, Cooper, C. A., additional, Cottier, K., additional, Galinski, M. R., additional, Harupa-Chung, A., additional, Ji, H., additional, Joseph, S. B., additional, Lenz, T., additional, Lonardi, S., additional, Matheson, J., additional, Mikolajczak, S. A., additional, Padín-Irizarry, V., additional, Pan, K., additional, Péneau, J., additional, Prudhomme, J., additional, Roesch, C., additional, Sabnis, S. S., additional, Saney, C. L., additional, Sattabongkot, J., additional, Sereshki, S., additional, Suriyakan, S., additional, Moeller, T., additional, Ubalee, R., additional, Wang, Y., additional, Wasisakun, P., additional, Yin, J., additional, McNamara, C. W., additional, Joyner, C. J., additional, Nosten, F., additional, Witkowski, B., additional, Le Roch, K. G., additional, and Kyle, D. E., additional

Published
2023
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3. A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria.

Author

Chahine Z, Abel S, Hollin T, Barnes GL, Chung JH, Daub ME, Renard I, Choi JY, Vydyam P, Pal A, Alba-Argomaniz M, Banks CAS, Kirkwood J, Saraf A, Camino I, Castaneda P, Cuevas MC, De Mercado-Arnanz J, Fernandez-Alvaro E, Garcia-Perez A, Ibarz N, Viera-Morilla S, Prudhomme J, Joyner CJ, Bei AK, Florens L, Ben Mamoun C, Vanderwal CD, and Le Roch KG

Subjects
Animals, Humans, Mice, Disease Models, Animal, Drug Resistance genetics, Mutation, Protozoan Proteins metabolism, Protozoan Proteins genetics, Antimalarials chemistry, Antimalarials pharmacology, Apicoplasts drug effects, Apicoplasts metabolism, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Plasmodium falciparum drug effects, Plasmodium falciparum genetics, Diterpenes chemistry, Diterpenes pharmacology
Abstract

We report the discovery of MED6-189, an analog of the kalihinol family of isocyanoterpene natural products that is effective against drug-sensitive and drug-resistant Plasmodium falciparum strains, blocking both asexual replication and sexual differentiation. In vivo studies using a humanized mouse model of malaria confirm strong efficacy of the compound in animals with no apparent hemolytic activity or toxicity. Complementary chemical, molecular, and genomics analyses revealed that MED6-189 targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses revealed that a mutation in PfSec13 , which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. Its high potency, excellent therapeutic profile, and distinctive mode of action make MED6-189 an excellent addition to the antimalarial drug pipeline.

Published
2024
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4. A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

Author

Maher SP, Bakowski MA, Vantaux A, Flannery EL, Andolina C, Gupta M, Antonova-Koch Y, Argomaniz M, Cabrera-Mora M, Campo B, Chao AT, Chatterjee AK, Cheng WT, Chuenchob E, Cooper CA, Cottier K, Galinski MR, Harupa-Chung A, Ji H, Joseph SB, Lenz T, Lonardi S, Matheson J, Mikolajczak SA, Moeller T, Orban A, Padín-Irizarry V, Pan K, Péneau J, Prudhomme J, Roesch C, Ruberto AA, Sabnis SS, Saney CL, Sattabongkot J, Sereshki S, Suriyakan S, Ubalee R, Wang Y, Wasisakun P, Yin J, Popovici J, McNamara CW, Joyner CJ, Nosten F, Witkowski B, Le Roch KG, and Kyle DE

Abstract

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax . The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials., Competing Interests: Competing interests: TM and KC are employees of BioIVT. AH-C, ELF, and SAM are employees of the Novartis Institute for Tropical Disease, BC is an employee of MMV. All other authors have no competing interests.

Published
2024
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5. A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in P. falciparum Malaria.

Author

Chahine Z, Abel S, Hollin T, Chung JH, Barnes GL, Daub ME, Renard I, Choi JY, Pratap V, Pal A, Alba-Argomaniz M, Banks C, Kirkwood J, Saraf A, Camino I, Castaneda P, Cuevas MC, De Mercado-Arnanz J, Fernandez-Alvaro E, Garcia-Perez A, Ibarz N, Viera-Morilla S, Prudhomme J, Joyner CJ, Bei AK, Florens L, Ben Mamoun C, Vanderwal CD, and Le Roch KG

Abstract

Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and -resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi . In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P. falciparum revealed that a mutation in PfSec13 , which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189 in vitro and in vivo , its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline., Competing Interests: Competing Interests-- The authors declare no competing interests. Correspondence and requests for materials should be addressed to Karine Le Roch.

Published
2023
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