Journal: J Med Chem / Year: 2020 Title: Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases. Authors: Advait Nagle / Agnes Biggart / Celine Be / Honnappa Srinivas / Andreas Hein / Diana Caridha / Richard J Sciotti / Brandon Pybus / Mara Kreishman-Deitrick / Badry Bursulaya / Yin H Lai / Mu- ...Authors: Advait Nagle / Agnes Biggart / Celine Be / Honnappa Srinivas / Andreas Hein / Diana Caridha / Richard J Sciotti / Brandon Pybus / Mara Kreishman-Deitrick / Badry Bursulaya / Yin H Lai / Mu-Yun Gao / Fang Liang / Casey J N Mathison / Xiaodong Liu / Vince Yeh / Jeffrey Smith / Isabelle Lerario / Yongping Xie / Donatella Chianelli / Michael Gibney / Ashley Berman / Yen-Liang Chen / Jan Jiricek / Lauren C Davis / Xianzhong Liu / Jaime Ballard / Shilpi Khare / Fabian Kurt Eggimann / Alexandre Luneau / Todd Groessl / Michael Shapiro / Wendy Richmond / Kevin Johnson / Patrick J Rudewicz / Srinivasa P S Rao / Christopher Thompson / Tove Tuntland / Glen Spraggon / Richard J Glynne / Frantisek Supek / Christian Wiesmann / Valentina Molteni / Abstract: Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we ...Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome.
History
Deposition
Nov 7, 2019
-
Header (metadata) release
Nov 27, 2019
-
Map release
Aug 26, 2020
-
Update
Dec 2, 2020
-
Current status
Dec 2, 2020
Processing site: PDBe / Status: Released
-
Structure visualization
Movie
Surface view with section colored by density value
In the structure databanks used in Yorodumi, some data are registered as the other names, "COVID-19 virus" and "2019-nCoV". Here are the details of the virus and the list of structure data.
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)
EMDB accession codes are about to change! (news from PDBe EMDB page)
The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
The EM Navigator/Yorodumi systems omit the EMD- prefix.
Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator
Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.
Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi