Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition

Susan Wyllie, Stephen Brand, Michael Thomas, Manu De Rycker, Chun-Wa Chung, Imanol Peña, Ryan Bingham, Juan Bueren-Calabuig, Juan Cantizani, David Cebrian, Peter D. Craggs, Liam Ferguson, Panchali Goswami, Judith Hobrath, Jonathan Howe, Laura Jeacock, Eun Jung Ko, Justyna Korczynska, Lorna MacLean, Sujatha ManthriMaria Santos Martinez, Lydia Mata-Cantero, Sonia Moniz, Andrea Nuhs, Maria Osuna-Cabello, Erika Pinto, Jennifer Riley, Sharon Robinson, Paul Rowland, Frederick Simeons, Yoko Shishikura, Daniel Spinks, Laste Stojanovski, John Thomas, Stephen Thompson, Elisabet Viayna Gaza, Richard Wall, Fabio Zuccotto, David Horn, Michael Ferguson, Alan Fairlamb, Jose M. Fiandor, Julio Martín, David Gray, Timothy J. Miles, Ian Gilbert, Kevin Read, Maria Marco, Paul Wyatt

Research output: Contribution to journalArticle

19 Citations (Scopus)
134 Downloads (Pure)

Abstract

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi. Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the β5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the β4 and β5 proteasome subunits. This induced pocket exploits β4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.

Original languageEnglish
Article number201820175
Pages (from-to)9318-9323
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume116
Issue number19
Early online date8 Apr 2019
DOIs
Publication statusPublished - 7 May 2019

Keywords

  • Cryo-EM
  • Drug discovery
  • Leishmania
  • Proteasome

Fingerprint Dive into the research topics of 'Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition'. Together they form a unique fingerprint.

  • Projects

    Profiles

    No photo of Kevin Read

    Read, Kevin

    Person: Academic

    Cite this

    Wyllie, S., Brand, S., Thomas, M., De Rycker, M., Chung, C-W., Peña, I., Bingham, R., Bueren-Calabuig, J., Cantizani, J., Cebrian, D., Craggs, P. D., Ferguson, L., Goswami, P., Hobrath, J., Howe, J., Jeacock, L., Ko, E. J., Korczynska, J., MacLean, L., ... Wyatt, P. (2019). Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition. Proceedings of the National Academy of Sciences, 116(19), 9318-9323. [201820175]. https://doi.org/10.1073/pnas.1820175116