Structure-Based Drug Development for Cryptosporidium and Other Parasites

Identifying and testing small molecule inhibitors of N-myristoyltransferase

Technology Overview

Dr. Bart StakerCryptosporidium parasites infect humans and animals. Infection can cause severe diarrhea and be life-threatening to people with immunosuppression because of HIV infection, genetic disease, cancer treatment, or transplantation. Cryptosporidiosis is the leading waterborne illness in the United States. Outbreaks are linked to pools and waterparks, childcare facilities, and interactions with animals. Reported outbreaks are increasing 13% annually in the United States. Cryptosporidium cysts can be resistant to chlorine treatment and few effective treatment options are available for this eukaryotic pathogen.

Dr. Bart Staker leads a project to identify small molecule drugs to treat cryptosporidiosis. The main target is N-myristoyltransferase (NMT), an enzyme that attaches a fatty acid modification to proteins, including targets unique to cryptosporidium. NMT inhibitors have the potential to become a novel class of drugs against a range of pathogens. Dr. Staker collaborated on work that validated NMT as a drug target for other parasites including the pathogens that cause malaria.

Using structure-based drug design methods, Dr. Staker’s team identified candidate molecules with high-affinity binding to NMT. In addition to using established in vitro testing methods to validate the candidate compounds, the researchers are developing mouse model assays for in vivo analysis of their effects. Drugs against cryptosporidium would have broad clinical and veterinary applications.

Dr. Staker’s association with the Center for Global Infectious Disease Research, and in particular the Seattle Structural Genomics Center for Infectious Disease (SSGCID), provides access to facilities, equipment, and additional expertise for structure-based drug design. SSGCID is a statewide consortium of academic, government, and industry collaborators that is identifying drug targets for emerging and re-emerging infectious diseases. SSGCID researchers are skilled in methods including X-ray crystallography, cryoelectron microscopy and NMR spectroscopy. The center has determined the structures of 1220 proteins that are potential drug and vaccine targets and continues to solve about 100 structures annually. The group is also experienced in curation and management of data, including data on protein structure and in vitro expression.

Dr. Staker’s professional experience includes 15 years in industry, in preclinical drug discovery. He founded two successful biotech companies and continues to work in public-private partnerships, including collaborations with small startups, medium-sized companies, and global industry partners. He is interested in partnerships that use his expertise in protein biochemistry to design new compounds to treat cryptosporidiosis and other parasitic diseases.

Stage of Development

• Pre-clinical in vitro and in vivo

Partnering Opportunities

• Collaborative research opportunity
• Sponsored research agreement
• Consultation agreement
• High throughput screening

Publications

1. Harupa A, De Las Heras L, Colmenarejo G, Lyons-Abbott S, Reers A, Caballero Hernandez I,...Staker BL...Identification of Selective Inhibitors of Plasmodium N-Myristoyltransferase by High-Throughput Screening.  J Med Chem. 2020 Jan 23;63(2):591-600. doi: 10.1021/acs.jmedchem.9b01343. Epub 2020 Jan 8.
2. Schlott AC, Mayclin S, Reers AR, Coburn-Flynn O, Bell AS,...Staker BL...Structure-guided identification of resistance breaking antimalarial N‑myristoyltransferase inhibitors. Cell Chem Biol. 2019;26(7):991-1000.e7. doi: 10.1016/j.chembiol.2019.03.015.
3. Cuypers B, Domagalska MA, Meysman P, Muylder G, Vanaerschot M, Imamura H, Dumetz F, Verdonckt TW, Myler PJ, Ramasamy G, Laukens K, Dujardin JC. Multiplexed spliced-leader sequencing: A high-throughput, selective method for RNA-seq in trypanosomatids. Sci Rep. 2017;7(1):3725. doi: 10.1038/s41598-017-03987-0.
4. Moen SO, Edwards TE, Dranow DM, Clifton MC, Sankaran B, Van Voorhis WC...Staker BL...Ligand co-crystallization of aminoacyl-tRNA synthetases from infectious disease organisms. Sci Rep. 2017;7(1):223. doi: 10.1038/s41598-017-00367-6.
5. Buchko GW, Abendroth J, Clifton MC, Robinson H, Zhang Y, Hewitt SN, Staker BL...Structure of a CutA1 divalent-cation tolerance protein from Cryptosporidium parvum, the protozoal parasite responsible for cryptosporidiosis. Acta Crystallogr F Struct Biol Commun. 2015;71(Pt 5):522-30. doi: 10.1107/S2053230X14028210.
6. Raymond A, Haffner T, Ng N, Lorimer D, Staker B, Stewart L. Gene design, cloning and protein-expression methods for high-value targets at the Seattle Structural Genomics Center for Infectious Disease. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011;67(Pt 9):992-7. doi: 10.1107/S1744309111026698.

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