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Structural Analysis and Inhibitor Optimization of Cryptosporidium n-myristoyltransferase for Drug Discovery

用于药物发现的隐孢子虫 n-肉豆蔻酰转移酶的结构分析和抑制剂优化

基本信息

批准号：
10095042
负责人：
Bart Lee Staker
金额：
$ 85.1万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-11-15 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10095042
关键词：
Affinity Aftercare Age Animal Model Animals Antiparasitic Agents Back Binding Biological Assay C14 isotope Case Study Characteristics Chemicals Child Childhood Communicable Diseases Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Crystallization Data Diarrhea Drug Design Drug Kinetics Drug Targeting Enzymes Fatty Acids Glycine Goals Human In Vitro Incidence Infection Insect Vectors Lead Leishmaniasis Libraries Malaria Malnutrition Measures Membrane Methods Modeling Mus Mutate Myristates N-myristoyltransferase N-terminal Oral Parasites Parasitic Diseases Parasitic infection Peptides Pharmaceutical Preparations Pharmacology and Toxicology Plasmodium Plasmodium falciparum Preclinical Drug Development Preparation Proteins Reporting Research Personnel Resistance Roentgen Rays Route Screening Result Series Solubility Staphylococcus hominis Structure Synthesis Chemistry Testing Time Toxoplasma Translating Work base design drug discovery drug synthesis druggable target effective therapy efficacy study gut colonization high throughput screening improved in vivo inhibitor/antagonist lead optimization lead series mouse model pre-clinical preclinical development programs scaffold screening

项目摘要

ABSTRACT Each year over 525,000 children under age five are killed by diarrhea caused by infectious disease. Cryptosporidiosis, the second most frequent cause of childhood diarrhea, is an infection caused by colonization of the intestines by the eukaryotic parasites, Cryptosporidium parvum or C. hominis, and particularly damages and kills malnourished children. In contrast to other Apicomplexans (such as Plasmodium or Toxoplasma), there is no required insect vector or animal host, since parasites can be transferred directly from human to human through the fecal-oral route. Despite the high incidence and significant impact on malnourished children, there are no effective treatments for cryptosporidiosis. We had previously screened the GSK Tres Cantos proprietary library of ~2 million compounds against P. falciparum N-myristoyltransferase (NMT). NMT is an enzyme which transfers myristate, a 14-carbon fatty acid, to the N-terminal glycine residue of proteins co-translationally, which contributes to targeting the substrate protein to membrane regions. NMT has been validated as a drug target in fungal and parasitic diseases, including malaria and leishmaniasis. We hypothesized that NMT high-throughput screening (HTS) hits effective against Plasmodium would also be active against Cryptosporidium and tested the top eight hits against Cryptosporidium parvum NMT (CpNMT). Of those top eight hits, three were effective against the purified enzyme and one showed activity against the parasite in vitro. A follow-on synthetic chemistry and structure- based drug design program further developed these hits into a lead series (called Series-2) of highly effective (~10nM IC50) inhibitors with 500-1000 X selectivity over the human enzyme. The two most promising leads from the Series-2 scaffold were then tested in a mouse model of infection and found that both molecules completely cleared infection. These data serve to chemically validate NMT as a druggable target for the treatment of Cryptosporidiosis. In this proposal we intend to further develop lead compounds in order to improve drug-like characteristics in preparation for preclinical drug development.

摘要