ABSTRACT
Artemisinin resistant Plasmodium falciparum (Pf) is spreading despite combination chemotherapy (ACT). Here we report the design of artezomibs, single-molecule hybrids of an artemisinin and a Pf-selective proteasome inhibitor. Artezomibs exert a novel mode of action inside the malaria parasites. The artemisinin component covalently modifies parasite proteins, which become substrates of the Pf proteasome. The proteasomal degradation products that bear the proteasome inhibitor component of the hybrid then inhibit Pf proteasomes, including those with mutations that reduce binding affinity of the proteasome inhibitor component on its own. We demonstrated that artezomibs circumvent both artemisinin resistance conferred by Kelch13 polymorphism and resistance to the proteasome inhibitor associated with mutations in Pf proteasomes. This mode of action may enable the use of a single molecule with one pharmacokinetic profile to prevent the emergence of resistance.
Competing Interest Statement
The authors declare the following competing financial interest(s): Cornell University has filed a provisional patent application on these artemisinin proteasome inhibitor hybrids. G. Lin, W. Zhan, H. Zhang, C. Nathan and L. Kirkman are listed as inventors. This statement will be revised once more information is available before publication.
ABBREVIATIONS
- ART
- artemisinin
- ACT
- artemisinin combination therapy
- ATZ
- artezomib – artemisinin-proteasome inhibitor hybrid
- c-20S
- human constitutive proteasome
- i-20S
- human immunoproteasome
- Pf
- Plasmodium falciparum
- Pf20S
- Pf proteasome
- Dd2(β6A117D)
- Pf Dd2 strain with a mutation A117D on β6 subunit of Pf20S
- Dd2(β5A49S)
- Pf Dd2 strain with a mutation A49S on β5 subunit of Pf20S;
- Pf20S(β6A117D)
- Pf20S with a mutation A117D on β6 subunit
- Pf20S(β5A49S)
- Pf20S with a mutation A49S on β5 subunit