Malaria: Host-based Drug Discovery for Infectious Diseases
Using in vitro, in vivo, and computational methods to find drugs and drug targets for bacterial, viral, and parasitic diseases
Infectious diseases are a major cause of global illness and death. Malaria parasites kill more than 400,000 people a year and children are particularly susceptible. Dr. Alexis Kaushansky studies host-pathogen interactions in diseases caused by parasites, bacteria, and viruses. Her goal is to identify factors in human host cells that are required by pathogens and are thus potential therapeutic targets. A host-based approach has the potential to identify pathways and factors involved in the infections of multiple pathogens, allowing for the development of drugs that are effective against multiple diseases. In addition, this strategy may reduce the development of drug-resistant pathogens.
Dr. Kaushansky’s group has, for example, discovered that some cancer drugs are also potent antimalarials because of overlap between the signaling pathways involved in carcinogenesis and in early, liver-stage malarial infection. The researchers performed in vitro tests for antimalarial effects on a small number of kinase inhibitor compounds, including some in clinical trials and some already approved for cancer treatment. Applying a computational method to the resulting data as well as to public datasets on human kinases, they were able to predict with 80% success other kinase inhibitors that can block malaria infection.
Dr. Kaushansky’s group also applied a machine-learning algorithm to their own and public data to identify human kinases involved in liver-stage malaria infection that could be new drug targets. This combined experimental-computational approach is applicable to host-based drug discovery for other diseases and could inform efficient compound selection and drug design.
Dr. Kaushansky has expertise in proteomics for drug discovery including the use of protein microarrays that require only picoliter samples to measure protein levels and detect post-translational modifications. Using this method, her team was able to show that levels of oncogenes and tumor suppressors are altered in infected cells in similar manners to their alterations in tumors. This observation led to the finding that multiple classes of drugs, including Bcl-2 inhibitors, a class of molecules that includes FDA-approved cancer drugs, have strong antimalarial effects. The Kaushansky group has expertise in infectious disease experiments with animal models and access to state-of-the-art insectaries for cultivating the mosquitoes that transmit malaria parasites to rodents and humans.
Stage of Development
- Pre-clinical in vitro
- Pre-clinical in vivo
- Sponsored research agreement
- Tissue sample access
- Target identification
- Drug screening
- Insectaries and mouse models
- Vijayan K, Cestari I, Mast FD, Glennon EKK...Kaushansky A., Plasmodium Secretion Induces Hepatocyte Lysosome Exocytosis and Promotes Parasite Entry. iScience. 2019 Nov 22;21:603-611. doi: 10.1016/j.isci.2019.10.054. Epub 2019 Oct 31.
- Tran TM, Guha R, Portugal S, Skinner J, Ongoiba A...Kaushansky A..., A Molecular Signature in Blood Reveals a Role for p53 in Regulating Malaria-Induced Inflammation., Immunity. 2019 Oct 15;51(4):750-765.e10. doi: 10.1016/vj.immuni.2019.08.009. Epub 2019 Sep 3.
- Kain HS, Glennon EKK, Vijayan K, Arang N, Douglass AN, Fortin CL...Kaushansky A., Liver stage malaria infection is controlled by host regulators of lipid peroxidation. Cell Death Differ. 2020 Jan;27(1):44-54. doi: 10.1038/s41418-019-0338-1. Epub 2019 May 7.
- Glennon EKK, Austin LS, Arang N, Kain HS, Mast FD, Vijayan K...Kaushansky A., Alterations in Phosphorylation of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection. Cell Rep. 2019 Mar 19;26(12):3391-3399.e4. doi: 10.1016/j.celrep.2019.02.085.
- Glennon EKK, Dankwa S, Smith JD, Kaushansky A. Opportunities for host-targeted therapies for malaria. Trends Parasit. 2018; 34:843-860.
- Arang N, Kain HS, Glennon EK, Bello T, Dudgeon DR, … Kaushansky A. Identifying host regulators and inhibitors of liver stage malaria infection using kinase activity profiles. Nature Communications. 2017: 1232.
- Douglass AN, Kain HS, Abdullahi M, Arang N, Austin LS, ... Kaushansky A. Host-based prophylaxis successfully targets liver stage malaria parasites. Mol Ther. 2015; 23: 857-865.