Killing two parasites with one stone

15-05-2019

Each year Malaria affects 219 million people, causing almost half a million deaths. Crysptosporidiosis is the leading cause of diarrheal diseases in infants, leading to 200,000 deaths a year. An international team of scientists, led by researchers at the University of Dundee, have discovered a molecule which clears the parasites that cause these two illnesses. Their results are published in PNAS.

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Malaria is a well-known disease caused by the parasites Plasmodium falciparum and Plamodium vivax and is the target of many available medications. However, the development of drug resistance has led the scientific community search for new therapeutic molecules which might provide for chemoprotection, prevention of transmission, and the treatment of relapsing malaria.

Like malaria, cryptosporidiosis is also a disease caused parasites, in this case Cryptosporidium hominis and Cryptosporidium parvum. Although it does not have the same ‘visibility as Malaria, Cryptosporidiosis is the leading cause worldwide of moderate-to-severe diarrheal diseases in infants and is estimated to lead to more than 200,000 deaths a year. The disease and is also associated with malnutrition, stunted growth, and cognitive-development problems in children. The currently approved drug, nitazoxanide, has poor efficacy, particularly in the case of immune-compromised patients and malnourished children, where there is no effective treatment.

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Binding modes of ligands bound to PfKRS1 and CpKRS. (A) PfKRS1:Lys:2 showing the binding mode of 2 (C atoms, gold) bound to the ATP site of PfKRS1 (PDB ID code 6AGT) superimposed upon PfKRS1:Lys:cladosporin (cladosporin C atoms, slate; PDB ID code 4PG3). (B) PfKRS1:5 showing binding mode of 5 bound to PfKRS1 (PDB ID code 6HCU). (C) Overlay of CpKRS:Lys:cladosporin (C atoms, gold; PDB ID code 5ELO) compared with PfKRS1:Lys:cladosporin (C atoms, gray; PDB ID code 4PG3). Nonconserved residues within the ligand binding site are labeled. (D) CpKRS:Lys:5 showing binding mode of 5 (C atoms, gold) in complex with CpKRS:Lys (C atoms, gray; PDB ID code 6HCW). H-bonds are shown as dashed lines, and key residues are labeled for clarity.

New treatments with novel mechanisms of action are clearly needed for both malaria and cryptosporidiosis. An international team of scientists has studied the natural product cladosporin, which is active against Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies and showed that in P. falciparum cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). They then set about identifying a new small molecule inhibitor of KRS1 that is active against both pathogens, then optimized its properties using a structure-based approach, supported by X-ray structure determination at the ESRF (BM14, ID29) as well as in-house. This resulting ‘lead compound’ can clear parasites from mouse models of malaria and cryptosporidiosis infection, validating the targeting of KRSs as a potential treatment against malaria and cryptosporidiosis. “This research provides a very strong validation of lysyl-tRNA synthetase as a drug target in these organisms and a lead for further drug discovery”, explains the team in their PNAS publication.

 “This work highlights the potential of structure-based design as a crucial tool in the development of new drugs and we expect such investigations to become a large part of the future activity on our beamlines”, explains Gordon Leonard, head of the Structural biology group at the ESRF.  

Reference

Baragaña, B. et al, PNAS April 2, 2019 116 (14) 7015-7020. https://doi.org/10.1073/pnas.1814685116

 

Top image: The mosquito Anopheles Gambiae, whose bite transmits malaria.