Citation: Anil Kumar Marapaka, Priyanka Sankoju, Guozhen Zhang, Yongzheng Ding, Chunhua Ma, Vijaykumar Pillalamarri, Renu Sudhakar, Bharati Reddi, Puran Singh Sijwali, Yingjie Zhang, Anthony Addlagatta. Development of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors: Biological evaluation and structural characterization by cocrystallization[J]. Chinese Chemical Letters, ;2022, 33(5): 2550-2554. doi: 10.1016/j.cclet.2021.09.102 shu

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

Anil Kumar Marapaka ^{a, b, c, 1} ,
Priyanka Sankoju ^{b, c, 1} ,
Guozhen Zhang ^{a, 1} ,
Yongzheng Ding ^{a, 1} ,
Chunhua Ma ^a ,
Vijaykumar Pillalamarri ^{b, c} ,
Renu Sudhakar ^d ,
Bharati Reddi ^{b, c} ,
Puran Singh Sijwali ^{d, *,} ,
Yingjie Zhang ^{a, *,} ,
Anthony Addlagatta ^{b, c, *,}

a.
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
b.
Department Applied Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana-500 007, India
c.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
d.
CSIR-Centre for Cellular and Molecular Biology, Tarnaka, Hyderabad, Telangana-500 007, India

zhangyingjie@sdu.edu.cn

anthony@csiriict.in

psijwali@ccmb.res.in

Received Date: 28 July 2021
Revised Date: 15 September 2021
Accepted Date: 29 September 2021
Available Online: 4 October 2021

Figures(2)

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 K_i = 0.11 ± 0.0002 µmol/L, PfA-M17 K_i = 0.05 ± 0.005 µmol/L), but also possesses remarkable selectivity over the mammalian counterpart (pAPN K_i = 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.
- Aminopeptidase,
- Dual inhibitor,
- Antimalaria,
- Peptidomimetic,
- Plasmodium falciparum
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