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

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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

Fingerprint

Leishmania infantum
Visceral Leishmaniasis
Proteasome Endopeptidase Complex
Leishmania donovani
Parasites
miltefosine
Neglected Diseases
Parasitic Diseases
Trypanosoma cruzi
Leishmania
Chymotrypsin
Mutagenesis
Pharmaceutical Preparations
Pharmacokinetics
Clinical Trials
Safety
Infection
Therapeutics

Keywords

  • Cryo-EM
  • Drug discovery
  • Leishmania
  • Proteasome

Cite this

Wyllie, Susan ; Brand, Stephen ; Thomas, Michael ; De Rycker, Manu ; Chung, Chun-Wa ; Peña, Imanol ; Bingham, Ryan ; Bueren-Calabuig, Juan ; Cantizani, Juan ; Cebrian, David ; Craggs, Peter D. ; Ferguson, Liam ; Goswami, Panchali ; Hobrath, Judith ; Howe, Jonathan ; Jeacock, Laura ; Ko, Eun Jung ; Korczynska, Justyna ; MacLean, Lorna ; Manthri, Sujatha ; Santos Martinez, Maria ; Mata-Cantero, Lydia ; Moniz, Sonia ; Nuhs, Andrea ; Osuna-Cabello, Maria ; Pinto, Erika ; Riley, Jennifer ; Robinson, Sharon ; Rowland, Paul ; Simeons, Frederick ; Shishikura, Yoko ; Spinks, Daniel ; Stojanovski, Laste ; Thomas, John ; Thompson, Stephen ; Viayna Gaza, Elisabet ; Wall, Richard ; Zuccotto, Fabio ; Horn, David ; Ferguson, Michael ; Fairlamb, Alan ; Fiandor, Jose M. ; Martín, Julio ; Gray, David ; Miles, Timothy J. ; Gilbert, Ian ; Read, Kevin ; Marco, Maria ; Wyatt, Paul. / Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition. In: Proceedings of the National Academy of Sciences. 2019 ; Vol. 116, No. 19. pp. 9318-9323.
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title = "Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition",
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.",
keywords = "Cryo-EM, Drug discovery, Leishmania, Proteasome",
author = "Susan Wyllie and Stephen Brand and Michael Thomas and {De Rycker}, Manu and Chun-Wa Chung and Imanol Pe{\~n}a and Ryan Bingham and Juan Bueren-Calabuig and Juan Cantizani and David Cebrian and Craggs, {Peter D.} and Liam Ferguson and Panchali Goswami and Judith Hobrath and Jonathan Howe and Laura Jeacock and Ko, {Eun Jung} and Justyna Korczynska and Lorna MacLean and Sujatha Manthri and {Santos Martinez}, Maria and Lydia Mata-Cantero and Sonia Moniz and Andrea Nuhs and Maria Osuna-Cabello and Erika Pinto and Jennifer Riley and Sharon Robinson and Paul Rowland and Frederick Simeons and Yoko Shishikura and Daniel Spinks and Laste Stojanovski and John Thomas and Stephen Thompson and {Viayna Gaza}, Elisabet and Richard Wall and Fabio Zuccotto and David Horn and Michael Ferguson and Alan Fairlamb and Fiandor, {Jose M.} and Julio Mart{\'i}n and David Gray and Miles, {Timothy J.} and Ian Gilbert and Kevin Read and Maria Marco and Paul Wyatt",
note = "Funding: Wellcome Trust (grants 092340, 100476, 105021, 203134/Z/16/Z, 204672/Z/16/Z).",
year = "2019",
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journal = "Proceedings of the National Academy of Sciences",
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Wyllie, S, Brand, S, Thomas, M, De Rycker, M, Chung, C-W, Peña, I, Bingham, R, Bueren-Calabuig, J, Cantizani, J, Cebrian, D, Craggs, PD, Ferguson, L, Goswami, P, Hobrath, J, Howe, J, Jeacock, L, Ko, EJ, Korczynska, J, MacLean, L, Manthri, S, Santos Martinez, M, Mata-Cantero, L, Moniz, S, Nuhs, A, Osuna-Cabello, M, Pinto, E, Riley, J, Robinson, S, Rowland, P, Simeons, F, Shishikura, Y, Spinks, D, Stojanovski, L, Thomas, J, Thompson, S, Viayna Gaza, E, Wall, R, Zuccotto, F, Horn, D, Ferguson, M, Fairlamb, A, Fiandor, JM, Martín, J, Gray, D, Miles, TJ, Gilbert, I, Read, K, Marco, M & Wyatt, P 2019, 'Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition', Proceedings of the National Academy of Sciences, vol. 116, no. 19, 201820175, pp. 9318-9323. https://doi.org/10.1073/pnas.1820175116, https://doi.org/10.1073/pnas.1820175116

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

In: Proceedings of the National Academy of Sciences, Vol. 116, No. 19, 201820175, 07.05.2019, p. 9318-9323.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition

AU - Wyllie, Susan

AU - Brand, Stephen

AU - Thomas, Michael

AU - De Rycker, Manu

AU - Chung, Chun-Wa

AU - Peña, Imanol

AU - Bingham, Ryan

AU - Bueren-Calabuig, Juan

AU - Cantizani, Juan

AU - Cebrian, David

AU - Craggs, Peter D.

AU - Ferguson, Liam

AU - Goswami, Panchali

AU - Hobrath, Judith

AU - Howe, Jonathan

AU - Jeacock, Laura

AU - Ko, Eun Jung

AU - Korczynska, Justyna

AU - MacLean, Lorna

AU - Manthri, Sujatha

AU - Santos Martinez, Maria

AU - Mata-Cantero, Lydia

AU - Moniz, Sonia

AU - Nuhs, Andrea

AU - Osuna-Cabello, Maria

AU - Pinto, Erika

AU - Riley, Jennifer

AU - Robinson, Sharon

AU - Rowland, Paul

AU - Simeons, Frederick

AU - Shishikura, Yoko

AU - Spinks, Daniel

AU - Stojanovski, Laste

AU - Thomas, John

AU - Thompson, Stephen

AU - Viayna Gaza, Elisabet

AU - Wall, Richard

AU - Zuccotto, Fabio

AU - Horn, David

AU - Ferguson, Michael

AU - Fairlamb, Alan

AU - Fiandor, Jose M.

AU - Martín, Julio

AU - Gray, David

AU - Miles, Timothy J.

AU - Gilbert, Ian

AU - Read, Kevin

AU - Marco, Maria

AU - Wyatt, Paul

N1 - Funding: Wellcome Trust (grants 092340, 100476, 105021, 203134/Z/16/Z, 204672/Z/16/Z).

PY - 2019/5/7

Y1 - 2019/5/7

N2 - 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.

AB - 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.

KW - Cryo-EM

KW - Drug discovery

KW - Leishmania

KW - Proteasome

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UR - https://discovery.dundee.ac.uk/en/publications/64a4d105-62ad-4941-9ff9-59a04f31a0ba

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DO - 10.1073/pnas.1820175116

M3 - Article

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AN - SCOPUS:85065622206

VL - 116

SP - 9318

EP - 9323

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 0027-8424

IS - 19

M1 - 201820175

ER -