A target safety assessment of the potential toxicological risks of targeting plasmepsin IX/X for the treatment of malaria
| Autor: | Jane Barber, Ruth A. Roberts, Jean-Pierre Valentin, Delphine Baud, Claire Sadler, Phumzile Sikakana |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Drug
Health Toxicology and Mutagenesis medicine.medical_treatment media_common.quotation_subject Plasmepsin Review Pharmacology Toxicology Plasmodium 03 medical and health sciences 0302 clinical medicine medicine 030304 developmental biology media_common chemistry.chemical_classification 0303 health sciences Protease biology business.industry Drug discovery biology.organism_classification medicine.disease Enzyme chemistry 030220 oncology & carcinogenesis Toxicity business Malaria |
| Zdroj: | Toxicol Res (Camb) |
| ISSN: | 2045-4538 |
| DOI: | 10.1093/toxres/tfaa106 |
| Popis: | The aspartic proteases plasmepsin IX/X are important antimalarial drug targets due to their specificity to the malaria parasite and their vital role as mediators of disease progression. Focusing on parasite-specific targets where no human homologue exists reduces the possibility of on-target drug toxicity. However, there is a risk of toxicity driven by inadequate selectivity for plasmepsins IX/X in Plasmodium over related mammalian aspartic proteases. Of these, CatD/E may be of most toxicological relevance as CatD is a ubiquitous lysosomal enzyme present in most cell types and CatE is found in the gut and in erythrocytes, the clinically significant site of malarial infection. Based on mammalian aspartic protease physiology and adverse drug reactions (ADRs) to FDA-approved human immunodeficiency virus (HIV) aspartic protease inhibitors, we predicted several potential toxicities including β-cell and congenital abnormalities, hypotension, hypopigmentation, hyperlipidaemia, increased infection risk and respiratory, renal, gastrointestinal, dermatological, and other epithelial tissue toxicities. These ADRs to the HIV treatments are likely to be a result of host aspartic protease inhibition due a lack of specificity for the HIV protease; plasmepsins are much more closely related to human CatD than to HIV proteinase. Plasmepsin IX/X inhibition presents an opportunity to specifically target Plasmodium as an effective antimalarial treatment, providing adequate selectivity can be obtained. Potential plasmepsin IX/X inhibitors should be assayed for inhibitory activity against the main human aspartic proteases and particularly CatD/E. An investigative rodent study conducted early in drug discovery would serve as an initial risk assessment of the potential hazards identified. |
| Databáze: | OpenAIRE |
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