Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti ‐malaria Activity in Humanized Mice

Development of a Highly SelectivePlasmodium falciparum Proteasome Inhibitor with Anti ‐malaria Activity in Humanized MiceDr. Wenhu Zhan,Dr. Hao Zhang,Dr. John Ginn,Annie Leung,Yi J. Liu,Dr. Mayako Michino,Dr. Akinori Toita,Dr. Rei Okamoto,Tzu ‐Tshin Wong,Dr. Toshihiro Imaeda,Dr. Ryoma Hara,Dr. Takafumi Yukawa,Sevil Chelebieva,Patrick K. Tumwebaze,Dr. Maria Jose Lafuente ‐Monasterio,Dr. Maria Santos Martinez ‐Martinez,Dr. Jeremie Vendome,Dr. Thijs Beumin,Dr. Kenjiro Sato,Dr. Kazuyoshi Aso,Prof.  Dr. Philip J. Rosenthal,Prof.  Dr. Roland A. Cooper,Dr. Peter T. Meinke,Prof.  Dr. Carl F. Nathan,Prof.  Dr. Laura A. Kirkman,Prof.  Dr. Gang Lin   Plasmodium falciparum proteasome (Pf20S) inhibitors are active againstPlasmodium at multiple stages —erythrocytic, gametocyte, liver, and gamete activation stages—indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission‐blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhib itor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time‐dependent inhibition of the β5 subunit of thePf20S, kills artemisinin ‐sensitive and artemisinin‐resistantP.  falciparum isolates in  vitro and reduces parasitemia in humanized,P.  falciparum‐infected mice. 
Source: Organometallic Current - Category: Chemistry Tags: Drug discovery Inhibitors malaria Peptide Modification Source Type: blogs