Author: Zhang, Hao ; Beuming, Thijs ; Yukawa, Takafumi ; Lin, Gang ; Chelebieva, Sevil ; Vendome, Jeremie ; Ginn, John ; Zhan, Wenhu ; Lafuente‐Monasterio, Maria Jose ; Rosenthal, Philip J. ; Sato, Kenjiro ; Meinke, Peter T. ; Hara, Ryoma ; Tumwebaze, Patrick K. ; Kirkman, Laura A. ; Imaeda, Toshihiro ; Leung, Annie ; Liu, Yi J. ; Cooper, Roland A. ; Aso, Kazuyoshi ; Nathan, Carl F. ; Wong, Tzu‐Tshin ; Toita, Akinori ; Martinez‐Martinez, Maria Santos ; Michino, Mayako ; Okamoto, Rei

AbstractPlasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium 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 inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time‐dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin‐sensitive and artemisinin‐resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum‐infected mice.

11 Jul 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

Improvement of Asparagine Ethylenediamines as Anti-malarial Plasmodium-Selective Proteasome Inhibitors

Q1 · MEDICINE

Article

Author: Harris, Jacob C. ; Cooper, Roland A. ; Tumwebaze, Patrick K. ; Zhan, Wenhu ; Ginn, John ; Zhang, Hao ; Rosenthal, Philip J. ; Kirkman, Laura A. ; Visone, Joseph ; Wong, Tzu-Tshin ; Ouellette, Tierra ; Okoro, Judith I. ; Wang, Rong ; Kafsack, Björn F. C. ; Sukenick, George ; Lin, Gang ; Scales, Ryan M. ; Singh, Pradeep K. ; Meinke, Peter T.

The Plasmodium proteasome (Pf20S) emerged as a target for antimalarials. Pf20S inhibitors are active at multiple stages of the parasite life cycle and synergize with artemisinins, suggesting that Pf20S inhibitors have potential to be prophylactic, therapeutic, and transmission blocking as well as are useful for combination therapy. We recently reported asparagine ethylenediamines (AsnEDAs) as immunoproteasome inhibitors and modified AsnEDAs as selective Pf20S inhibitors. Here, we report further a structure-activity relationship study of AsnEDAs for selective inhibition of Pf20S over human proteasomes. Additionally, we show new mutation that conferred resistance to AsnEDAs and collateral sensitivity to an inhibitor of the Pf20S β2 subunit, the same as previously identified resistant mutation. This resistance could be overcome through the use of the structure-guided inhibitor design. Collateral sensitivity to inhibitors among respective proteasome subunits underscores the potential value of treating malaria with combinations of inhibitors of different proteasome subunits to minimize the emergence of drug resistance.

Nature CommunicationsQ1 · CROSS-FIELD

Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors

Q1 · CROSS-FIELD

ArticleOA

Author: Hsu, Hao-Chi ; Zhan, Wenhu ; Roth, Alison ; Zhang, Hao ; Crespo, Benigno ; Liu, Yi Jing ; Gamo, Francisco-Javier ; Lin, Gang ; Cui, Liwang ; Qin, Junling ; Kirkman, Laura A ; Ye, Jianxiang ; Leung, Annie ; Li, Huilin ; Li, Daqiang

AbstractThe proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with artemisinins. We recently developed a macrocyclic peptide, TDI-8304, that is highly selective for Pf20S over human proteasomes and is potent in vitro and in vivo against P. falciparum. A mutation in the Pf20S β6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone β2 inhibitor, WLW-vs. Here we present the high-resolution cryo-EM structures of Pf20S with TDI-8304, of human constitutive proteasome with TDI-8304, and of Pf20Sβ6A117D with WLW-vs that give insights into the species selectivity of TDI-8304, resistance to it, and the collateral sensitivity associated with resistance, including that TDI-8304 binds β2 and β5 in wild type Pf20S as well as WLW-vs binds β2 and β5 in Pf20Sβ6A117D. We further show that TDI-8304 kills P. falciparum as quickly as chloroquine and artemisinin and is active against P. cynomolgi at the liver stage. This increases interest in using these structures to facilitate the development of Pf20S inhibitors that target multiple proteasome subunits and limit the emergence of resistance.

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

Pf20S

Basic Info

Related

Analysis