Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors
Hao Zhang, John D. Ginn, Wenhu Zhan, Yi J. Liu, Annie Leung, Akinori Toita, Rei Okamoto, Tzu‐Tshin Wong, Toshihiro Imaeda, Ryoma Hara, Takafumi Yukawa, Mayako Michino, Jérémie Vendôme, Thijs Beuming, Kenjiro Sato, Kazuyoshi Aso, Peter T. Meinke, Carl Nathan, Laura A. Kirkman, Gang Lin
Abstract
With over 200 million cases and close to half a million deaths each year, malaria is a threat to global health, particularly in developing countries. Plasmodium falciparum, the parasite that causes the most severe form of the disease, has developed resistance to all antimalarial drugs. Resistance to the first-line antimalarial artemisinin and to artemisinin combination therapies is widespread in Southeast Asia and is emerging in sub-Saharan Africa. The P. falciparum proteasome is an attractive antimalarial target because its inhibition kills the parasite at multiple stages of its life cycle and restores artemisinin sensitivity in parasites that have become resistant through mutation in Kelch K13. Here, we detail our efforts to develop noncovalent, macrocyclic peptide malaria proteasome inhibitors, guided by structural analysis and pharmacokinetic properties, leading to a potent, species-selective, metabolically stable inhibitor.