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

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

UR - https://www.scopus.com/pages/publications/85065622206

U2 - 10.1073/pnas.1820175116

DO - 10.1073/pnas.1820175116

M3 - Article

C2 - 30962368

AN - SCOPUS:85065622206

SN - 0027-8424

VL - 116

SP - 9318

EP - 9323

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

IS - 19

M1 - 201820175

ER -