| Autor: |
Puran Singh Sijwali, Yongzheng Ding, Chunhua Ma, Vijaykumar Pillalamarri, Priyanka Sankoju, Yingjie Zhang, Bharati Reddi, Anil Kumar Marapaka, Guozhen Zhang, Anthony Addlagatta, Renu Sudhakar |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Chinese Chemical Letters. 33:2550-2554 |
| ISSN: |
1001-8417 |
| DOI: |
10.1016/j.cclet.2021.09.102 |
| Popis: |
Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use, including the artemisinin-based combinations, which are the last line of defense against malaria. This necessitates the discovery of new targets and the development of novel antimalarials. Plasmodium falciparum alanyl aminopeptidase (PfA-M1) and leucyl aminopeptidase (PfA-M17) belong to the M1 and M17 family of metalloproteases respectively and play critical roles in the asexual erythrocytic stage of development. These enzymes have been suggested as potential antimalarial drug targets. Herein we describe the development of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors. Most of the compounds described in this study display inhibition at sub-micromolar range against the recombinant PfA-M1 and PfA-M17. More importantly, compound 26 not only exhibits potent malarial aminopeptidases inhibitory activities (PfA-M1 Ki = 0.11 ± 0.0002 μmol/L, PfA-M17 Ki = 0.05 ± 0.005 μmol/L), but also possesses remarkable selectivity over the mammalian counterpart (pAPN Ki = 17.24 ± 0.08 μmol/L), which endows 26 with strong inhibition of the malarial parasite growth and negligible cytotoxicity on human cell lines. Crystal structures of PfA-M1 at atomic resolution in complex with four different compounds including compound 26 establish the structural basis for their inhibitory activities. Notably, the terminal ureidobenzyl group of 26 explores the S2’ region where differences between the malarial and mammalian enzymes are apparent, which rationalizes the selectivity of 26. Together, our data provide important insights for the rational and structure-based design of selective and dual inhibitors of malarial aminopeptidases that will likely lead to novel chemotherapeutics for the treatment of malaria. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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