Development of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors: Biological evaluation and structural characterization by cocrystallization  

作　　者：Anil Kumar Marapaka Priyanka Sankoju Guozhen Zhang Yongzheng Ding Chunhua Ma Vijaykumar Pillalamarri Renu Sudhakar Bharati Reddi Puran Singh Sijwali Yingjie Zhang Anthony Addlagatta 

机构地区：[1]Department of Medicinal Chemistry,Key Laboratory of Chemical Biology(Ministry of Education),School of Pharmaceutical Sciences,Cheeloo College of Medicine,Shandong University,Ji’nan 250012,China [2]Department Applied Biology,CSIR-Indian Institute of Chemical Technology,Tarnaka,Hyderabad,Telangana-500007,India [3]Academy of Scientific and Innovative Research(AcSIR),Ghaziabad-201002,India [4]CSIR-Centre for Cellular and Molecular Biology,Tarnaka,Hyderabad,Telangana-500007,India

出　　处：《Chinese Chemical Letters》2022年第5期2550-2554,共5页中国化学快报（英文版）

基　　金：supported by University Grants Commission (UGC), New Delhi, India and Bharati Reddi by Department of Science and Technology, New Delhi, India for their research fellowships;CSIR-IICT manuscript number is IICT/Pubs./2018/299;Anthony Addlagatta thanks Science and Engineering Research Board (SERB), New Delhi, India for research grants (Nos. EMR/2015/000461 and CRG/2019/006013);Natural Science Foundation of Shandong Province (No. ZR2018QH007, China);Key Research and Development Program of Shandong Province (No. 2017CXGC1401, China);Young Scholars Program of Shandong University (No. YSPSDU, 2016WLJH33, China) for research fellowships;Renu Sudhakar is the recipient of the fellowship from the Department of Biotechnology (India);Puran Singh Sijwali lab is supported with funds from the Department of Biotechnology, India (Nos. SR/SO/BB/-0124/2012 and BT/COE/34/SP15138/2015);the Council of Scientific & Industrial Research, India

摘　　要：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.

关 键 词：AMINOPEPTIDASE Dual inhibitor ANTIMALARIA PEPTIDOMIMETIC Plasmodium falciparum 

分 类 号：TQ460.1[化学工程—制药化工] R914[医药卫生—药物化学]