Identification of and Structural Insights into Hit Compounds Targeting N-Myristoyltransferase for Cryptosporidium Drug Development

Fenwick, Michael K.; Reers, Alexandra R.; Liu, Yi; Zigweid, Rachael; Sankaran, Banumathi; Shin, Janis; Hulverson, Matthew A.; Hammerson, Bradley; Fernández Álvaro, Elena; Myler, Peter J.; Kaushansky, Alexis; Van Voorhis, Wesley C.; Fan, Erkang; Staker, Bart L.

doi:10.1021/acsinfecdis.3c00151

Identification of and Structural Insights into Hit Compounds Targeting N-Myristoyltransferase for Cryptosporidium Drug Development

Journal Article · Mon Sep 18 00:00:00 EDT 2023 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.3c00151· OSTI ID:2280924

Fenwick, Michael K. ^[1]; Reers, Alexandra R. ^[2]; ^[3]; Zigweid, Rachael ^[2]; Sankaran, Banumathi ^[4]; ^[2]; ^[3]; Hammerson, Bradley ^[2]; Fernández Álvaro, Elena ^[5]; Myler, Peter J. ^[6]; ^[7]; Van Voorhis, Wesley C. ^[8]; Fan, Erkang ^[3]; ^[2]

Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States)
Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Seattle Children’s Research Institute, WA (United States)
Univ. of Washington, Seattle, WA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
GSK Global Health (Spain)
Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Seattle Children’s Research Institute, WA (United States); Univ. of Washington, Seattle, WA (United States)
Seattle Children’s Research Institute, WA (United States); Univ. of Washington, Seattle, WA (United States)
Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Washington, Seattle, WA (United States)

Each year, approximately 50,000 children under 5 die as a result of diarrhea caused by Cryptosporidium parvum, a protozoan parasite. There are currently no effective drugs or vaccines available to cure or prevent Cryptosporidium infection, and there are limited tools for identifying and validating targets for drug or vaccine development. We previously reported a high throughput screening (HTS) of a large compound library against Plasmodium N-myristoyltransferase (NMT), a validated drug target in multiple protozoan parasite species. To identify molecules that could be effective against Cryptosporidium, we counter-screened hits from the Plasmodium NMT HTS against Cryptosporidium NMT. We identified two potential hit compounds and validated them against CpNMT to determine if NMT might be an attractive drug target also for Cryptosporidium. We tested the compounds against Cryptosporidium using both cell-based and NMT enzymatic assays. We then determined the crystal structure of CpNMT bound to Myristoyl-Coenzyme A (MyrCoA) and structures of ternary complexes with MyrCoA and the hit compounds to identify the ligand binding modes. The binding site architectures display different conformational states in the presence of the two inhibitors and provide a basis for rational design of selective inhibitors.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2280924

Journal Information:: ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 10 Vol. 9; ISSN 2373-8227

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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