期刊文献+
共找到1篇文章
< 1 >
每页显示 20 50 100
Development of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors: Biological evaluation and structural characterization by cocrystallization
1
作者 Anil Kumar Marapaka Priyanka Sankoju +8 位作者 Guozhen Zhang Yongzheng Ding Chunhua Ma Vijaykumar Pillalamarri Renu Sudhakar bharati reddi Puran Singh Sijwali Yingjie Zhang Anthony Addlagatta 《Chinese Chemical Letters》 SCIE CAS CSCD 2022年第5期2550-2554,共5页
Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use,in-cluding the artemisinin-based combinations,which are the last line of defense against malaria.This ne-cessitates th... Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use,in-cluding the artemisinin-based combinations,which are the last line of defense against malaria.This ne-cessitates 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 devel-opment 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 K i=0.11±0.0002μmol/L,PfA-M17 K_(i)=0.05±0.005μmol/L),but also possesses remarkable selectivity over the mammalian counterpart(pAPN K_(i)=17.24±0.08μmol/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 ureidoben-zyl 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. 展开更多
关键词 AMINOPEPTIDASE Dual inhibitor ANTIMALARIA PEPTIDOMIMETIC Plasmodium falciparum
原文传递
上一页 1 下一页 到第
使用帮助 返回顶部