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Identification of and Structural Insights into Hit Compounds Targeting N-Myristoyltransferase for Cryptosporidium
Michael K Fenwick1, Alexandra R Reers1,2, Yi Liu3
1Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, Washington 98109, United States.
Insights
Researchers identified two potential drug compounds targeting Cryptosporidium N-myristoyltransferase (NMT), a key enzyme in the parasite. This discovery offers a promising avenue for developing new treatments against Cryptosporidium infections.
Area of Science:
- Parasitology
- Drug Discovery
- Structural Biology
Background:
- Cryptosporidium parvum causes fatal diarrhea in 50,000 children annually.
- No effective drugs or vaccines exist for Cryptosporidium infection.
- Limited tools hinder drug target identification for this parasite.
Purpose of the Study:
- To identify potential drug candidates against Cryptosporidium by screening against its N-myristoyltransferase (NMT).
- To validate NMT as a potential drug target for Cryptosporidium.
- To understand the binding mechanisms of inhibitors for rational drug design.
Main Methods:
- Counter-screening of Plasmodium NMT high-throughput screening hits against Cryptosporidium NMT.
- Cell-based and enzymatic assays to validate hit compounds.
- Determining crystal structures of Cryptosporidium NMT (CpNMT) with ligands and inhibitors.
Main Results:
- Two hit compounds were identified and validated against CpNMT.
- Structural analysis revealed distinct ligand binding modes and conformational states.
- The findings support NMT as a viable drug target for Cryptosporidium.
Conclusions:
- N-myristoyltransferase is a promising drug target for treating Cryptosporidium infections.
- Identified compounds and structural data provide a foundation for developing novel anti-parasitic drugs.
- Further research can leverage these findings for rational drug design against Cryptosporidium.
Abstract:
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.
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