9 results on '"Cowman, Alan F."'
Search Results
2. Activity refinement of aryl amino acetamides that target the P. falciparum STAR-related lipid transfer 1 protein
- Author
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Nguyen, William, Boulet, Coralie, Dans, Madeline G., Loi, Katie, Jarman, Kate E., Watson, Gabrielle M., Tham, Wai-Hong, Fairhurst, Kate J., Yeo, Tomas, Fidock, David A., Wittlin, Sergio, Chowdury, Mrittika, de Koning-Ward, Tania F., Chen, Gong, Yan, Dandan, Charman, Susan A., Baud, Delphine, Brand, Stephen, Jackson, Paul F., Cowman, Alan F., Gilson, Paul R., and Sleebs, Brad E.
- Published
- 2024
- Full Text
- View/download PDF
3. Property and Activity Refinement of Dihydroquinazolinone-3-carboxamides as Orally Efficacious Antimalarials that Target PfATP4
- Author
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Ashton, Trent D., Calic, Petar P. S., Dans, Madeline G., Ooi, Zi Kang, Zhou, Qingmiao, Palandri, Josephine, Loi, Katie, Jarman, Kate E., Qiu, Deyun, Lehane, Adele M., Maity, Bikash Chandra, De, Nirupam, Giannangelo, Carlo, MacRaild, Christopher A., Creek, Darren J., Mao, Emma Y., Gancheva, Maria R., Wilson, Danny W., Chowdury, Mrittika, de Koning-Ward, Tania F., Famodimu, Mufuliat T., Delves, Michael J., Pollard, Harry, Sutherland, Colin J., Baud, Delphine, Brand, Stephen, Jackson, Paul F., Cowman, Alan F., and Sleebs, Brad E.
- Abstract
To contribute to the global effort to develop new antimalarial therapies, we previously disclosed initial findings on the optimization of the dihydroquinazolinone-3-carboxamide class that targets PfATP4. Here we report on refining the aqueous solubility and metabolic stability to improve the pharmacokinetic profile and consequently in vivo efficacy. We show that the incorporation of heterocycle systems in the 8-position of the scaffold was found to provide the greatest attainable balance between parasite activity, aqueous solubility, and metabolic stability. Optimized analogs, including the frontrunner compound S-WJM992, were shown to inhibit PfATP4-associated Na+-ATPase activity, gave rise to a metabolic signature consistent with PfATP4 inhibition, and displayed altered activities against parasites with mutations in PfATP4. Finally, S-WJM992 showed appreciable efficacy in a malaria mouse model and blocked gamete development preventing transmission to mosquitoes. Importantly, further optimization of the dihydroquinazolinone class is required to deliver a candidate with improved pharmacokinetic and risk of resistance profiles.
- Published
- 2024
- Full Text
- View/download PDF
4. Flp/FRT-mediated disruption of ptex150 and exp2 in Plasmodium falciparum sporozoites inhibits liver-stage development.
- Author
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McConville, Robyn, Krol, Jelte M. M., Steel, Ryan W. J., O'Neill, Matthew T., Davey, Bethany K., Hodder, Anthony N., Nebl, Thomas, Cowman, Alan F., Kneteman, Norman, and Boddey, Justin A.
- Subjects
PLASMODIUM falciparum ,SPOROZOITES ,CIRCUMSPOROZOITE protein ,LIVER proteins ,PLASMODIUM berghei - Abstract
Plasmodium falciparum causes severe malaria and assembles a protein translocon (PTEX) complex at the parasitophorous vacuole membrane (PVM) of infected erythrocytes, through which several hundred proteins are exported to facilitate growth. The preceding liver stage of infection involves growth in a hepatocyte-derived PVM; however, the importance of protein export during P. falciparum liver infection remains unexplored. Here, we use the FlpL/FRT system to conditionally excise genes in P. falciparum sporozoites for functional liver-stage studies. Disruption of PTEX members ptex150 and exp2 did not affect sporozoite development in mosquitoes or infectivity for hepatocytes but attenuated liver-stage growth in humanized mice. While PTEX150 deficiency reduced fitness on day 6 postinfection by 40%, EXP2 deficiency caused 100% loss of liver parasites, demonstrating that PTEX components are required for growth in hepatocytes to differing degrees. To characterize PTEX loss-of-function mutations, we localized four liver-stage Plasmodium export element (PEXEL) proteins. P. falciparum liver specific protein 2 (LISP2), liver-stage antigen 3 (LSA3), circumsporozoite protein (CSP), and a Plasmodium berghei LISP2 reporter all localized to the periphery of P. falciparum liver stages but were not exported beyond the PVM. Expression of LISP2 and CSP but not LSA3 was reduced in ptex150-FRT and exp2-FRT liver stages, suggesting that expression of some PEXEL proteins is affected directly or indirectly by PTEX disruption. These results show that PTEX150 and EXP2 are important for P. falciparum development in hepatocytes and emphasize the emerging complexity of PEXEL protein trafficking. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
5. Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b.
- Author
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Awalt JK, Su W, Nguyen W, Loi K, Jarman KE, Penington JS, Ramesh S, Fairhurst KJ, Yeo T, Park H, Uhlemann AC, Chandra Maity B, De N, Mukherjee P, Chakraborty A, Churchyard A, Famodimu MT, Delves MJ, Baum J, Mittal N, Winzeler EA, Papenfuss AT, Chowdury M, de Koning-Ward TF, Maier AG, van Dooren GG, Baud D, Brand S, Fidock DA, Jackson PF, Cowman AF, Dans MG, and Sleebs BE
- Abstract
Drug resistance against antimalarials is rendering them increasingly ineffective and so there is a need for the development of new antimalarials. To discover new antimalarial chemotypes a phenotypic screen of the Janssen Jumpstarter library against the P. falciparum asexual stage was undertaken, uncovering the cyclopropyl carboxamide structural hit class. Structure-activity analysis revealed that each structural moiety was largely resistant to change, although small changes led to the frontrunner compound, WJM280, which has potent asexual stage activity (EC
50 40 nM) and no human cell cytotoxicity. Forward genetics uncovered that cyclopropyl carboxamide resistant parasites have mutations and an amplification in the cytochrome b gene. Cytochrome b was then verified as the target with profiling against cytochrome b drug-resistant parasites and a mitochondrial oxygen consumption assay. Accordingly, the cyclopropyl carboxamide class was shown to have slow-acting asexual stage activity and activity against male gametes and exoerythrocytic forms. Enhancing metabolic stability to attain efficacy in malaria mouse models remains a challenge in the future development of this antimalarial chemotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
6. Author Correction: Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1.
- Author
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Dans MG, Boulet C, Watson GM, Nguyen W, Dziekan JM, Evelyn C, Reaksudsan K, Mehra S, Razook Z, Geoghegan ND, Mlodzianoski MJ, Goodman CD, Ling DB, Jonsdottir TK, Tong J, Famodimu MT, Kristan M, Pollard H, Stewart LB, Brandner-Garrod L, Sutherland CJ, Delves MJ, McFadden GI, Barry AE, Crabb BS, de Koning-Ward TF, Rogers KL, Cowman AF, Tham WH, Sleebs BE, and Gilson PR
- Published
- 2024
- Full Text
- View/download PDF
7. Lactam Truncation Yields a Dihydroquinazolinone Scaffold with Potent Antimalarial Activity that Targets PfATP4.
- Author
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Ashton TD, Calic PPS, Dans MG, Ooi ZK, Zhou Q, Loi K, Jarman KE, Palandri J, Qiu D, Lehane AM, Maity B, De N, Famodimu MT, Delves MJ, Mao EY, Gancheva MR, Wilson DW, Chowdury M, de Koning-Ward TF, Baud D, Brand S, Jackson PF, Cowman AF, and Sleebs BE
- Abstract
The emergence of resistance against current antimalarial treatments has necessitated the need for the development of novel antimalarial chemotypes. Toward this goal, we recently optimised the antimalarial activity of the dihydroquinazolinone scaffold and showed it targeted PfATP4. Here, we deconstruct the lactam moiety of the tricyclic dihydroquinazolinone scaffold and investigate the structure-activity relationship of the truncated scaffold. It was shown that SAR between scaffolds was largely transferrable and generated analogues with potent asexual stage activity. Evaluation of the truncated analogues against PfATP4 mutant drug resistant parasite strains and in assays measuring PfATP4-associated ATPase activity demonstrated retention of PfATP4 as the molecular target. Analogues exhibited activity against both male and female gametes and multidrug resistant parasites. Limited efficacy of analogues in a P. berghei asexual stage mouse model was attributed to their moderate metabolic stability and low aqueous stability. Further development is required to address these attributes toward the potential use of the dihydroquinazolinone class in a curative and transmission blocking combination antimalarial therapy., (© 2024 Wiley‐VCH GmbH.)
- Published
- 2024
- Full Text
- View/download PDF
8. Flp/ FRT -mediated disruption of ptex150 and exp2 in Plasmodium falciparum sporozoites inhibits liver-stage development.
- Author
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McConville R, Krol JMM, Steel RWJ, O'Neill MT, Davey BK, Hodder AN, Nebl T, Cowman AF, Kneteman N, and Boddey JA
- Subjects
- Animals, Mice, Humans, Plasmodium falciparum growth & development, Plasmodium falciparum genetics, Plasmodium falciparum metabolism, Protozoan Proteins metabolism, Protozoan Proteins genetics, Sporozoites metabolism, Sporozoites growth & development, Liver parasitology, Liver metabolism, Hepatocytes parasitology, Hepatocytes metabolism, Malaria, Falciparum parasitology
- Abstract
Plasmodium falciparum causes severe malaria and assembles a protein translocon (PTEX) complex at the parasitophorous vacuole membrane (PVM) of infected erythrocytes, through which several hundred proteins are exported to facilitate growth. The preceding liver stage of infection involves growth in a hepatocyte-derived PVM; however, the importance of protein export during P. falciparum liver infection remains unexplored. Here, we use the FlpL/ FRT system to conditionally excise genes in P. falciparum sporozoites for functional liver-stage studies. Disruption of PTEX members ptex150 and exp2 did not affect sporozoite development in mosquitoes or infectivity for hepatocytes but attenuated liver-stage growth in humanized mice. While PTEX150 deficiency reduced fitness on day 6 postinfection by 40%, EXP2 deficiency caused 100% loss of liver parasites, demonstrating that PTEX components are required for growth in hepatocytes to differing degrees. To characterize PTEX loss-of-function mutations, we localized four liver-stage Plasmodium export element (PEXEL) proteins. P. falciparum liver specific protein 2 (LISP2), liver-stage antigen 3 (LSA3), circumsporozoite protein (CSP), and a Plasmodium berghei LISP2 reporter all localized to the periphery of P. falciparum liver stages but were not exported beyond the PVM. Expression of LISP2 and CSP but not LSA3 was reduced in ptex150-FRT and exp2-FRT liver stages, suggesting that expression of some PEXEL proteins is affected directly or indirectly by PTEX disruption. These results show that PTEX150 and EXP2 are important for P. falciparum development in hepatocytes and emphasize the emerging complexity of PEXEL protein trafficking., Competing Interests: Competing interests statement:The authors declare no competing interest.
- Published
- 2024
- Full Text
- View/download PDF
9. Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1.
- Author
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Dans MG, Boulet C, Watson GM, Nguyen W, Dziekan JM, Evelyn C, Reaksudsan K, Mehra S, Razook Z, Geoghegan ND, Mlodzianoski MJ, Goodman CD, Ling DB, Jonsdottir TK, Tong J, Famodimu MT, Kristan M, Pollard H, Stewart LB, Brandner-Garrod L, Sutherland CJ, Delves MJ, McFadden GI, Barry AE, Crabb BS, de Koning-Ward TF, Rogers KL, Cowman AF, Tham WH, Sleebs BE, and Gilson PR
- Subjects
- Animals, Carrier Proteins metabolism, Carrier Proteins genetics, Mutation, Malaria, Falciparum parasitology, Malaria, Falciparum prevention & control, Malaria, Falciparum drug therapy, Humans, Drug Resistance genetics, Drug Resistance drug effects, Life Cycle Stages drug effects, Plasmodium falciparum drug effects, Plasmodium falciparum genetics, Plasmodium falciparum metabolism, Plasmodium falciparum growth & development, Acetamides pharmacology, Acetamides chemistry, Protozoan Proteins metabolism, Protozoan Proteins genetics, Antimalarials pharmacology, Antimalarials chemistry
- Abstract
With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite's lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
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