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
1. [1]
  B. Mills, R.E. Isaac, R. Foster, J. Med. Chem. 64 (2021) 1763-1785. doi: 10.1021/acs.jmedchem.0c01721
2. [2]
  World Health Organization. World Malaria Report 2020; Geneva, 2020. https://www.who.int/teams/global-malaria-programme/reports/worldmalaria-report-2020/.
3. [3]
  Z. Kifle, Infect. Drug Resist. 13 (2020) 4047-4060. doi: 10.2147/IDR.S279433
4. [4]
  D.E. Goldberg, A.F. Slater, A. Cerami, G.B. Henderson, Proc. Natl. Acad. Sci. U. S. A. 87 (1990) 2931-2935. doi: 10.1073/pnas.87.8.2931
5. [5]
  J. Liu, E.S. Istvan, I.Y. Gluzman, J. Gross, D.E. Goldberg, Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 8840-8845. doi: 10.1073/pnas.0601876103
6. [6]
  S. McGowan, Curr. Opin. Struct. Biol. 23 (2013) 828-835. doi: 10.1016/j.sbi.2013.07.015
7. [7]
  S.M. Marcin Poreba, T.S. Skinner-Adams, K.R. Trenholme, et al., PLoS One 7 (2012) e31938. doi: 10.1371/journal.pone.0031938
8. [8]
  S. Dalal, M. Klemba, J. Biol. Chem. 282 (2007) 35978-35987. doi: 10.1074/jbc.M703643200
9. [9]
  M.B. Harbut, G. Velmourougane, S. Dalal, et al., Proc. Natl. Acad. Sci. U. S. A. 108 (2011) E526-E534.
10. [10]
  R. Deprez-Poulain, M. Flipo, C. Piveteau, et al., J. Med. Chem. 55 (2012) 10909-10917. doi: 10.1021/jm301506h
11. [11]
  M. Flipo, T. Beghyn, V. Leroux, et al., J. Med. Chem. 50 (2007) 1322-1334. doi: 10.1021/jm061169b
12. [12]
  N.B. Vinh, N. Drinkwater, T.R. Malcolm, et al., J. Med. Chem. 62 (2019) 622-640. doi: 10.1021/acs.jmedchem.8b01310
13. [13]
  S.N. Mistry, N. Drinkwater, C. Ruggeri, et al., J. Med. Chem. 57 (2014) 9168-9183. doi: 10.1021/jm501323a
14. [14]
  T.S. Skinner-Adams, C.L. Peatey, K. Anderson, et al., Antimicrob. Agents Chemother. 56 (2012) 3244-3249. doi: 10.1128/AAC.06245-11
15. [15]
  N. Drinkwater, N.B. Vinh, S.N. Mistry, et al., Eur. J. Med. Chem. 110 (2016) 43-64. doi: 10.1016/j.ejmech.2016.01.015
16. [16]
  C. Ruggeri, N. Drinkwater, K.K. Sivaraman, et al., PLoS One 10 (2015) e0138957. doi: 10.1371/journal.pone.0138957
17. [17]
  K.K. Sivaraman, A. Paiardini, M. Sienczyk, et al., J. Med. Chem. 56 (2013) 5213-5217. doi: 10.1021/jm4005972
18. [18]
  E. Cunningham, M. Drag, P. Kafarski, A. Bell, Antimicrob. Agents Chemother. 52 (2008) 3221-3228. doi: 10.1128/AAC.01327-07
19. [19]
  T.S. Skinner-Adams, J. Lowther, F. Teuscher, et al., J. Med. Chem. 50 (2007) 6024-6031. doi: 10.1021/jm070733v
20. [20]
  E. Salomon, M. Schmitt, E. Mouray, et al., Bioorg. Chem. 98 (2020) 103750. doi: 10.1016/j.bioorg.2020.103750
21. [21]
  L. Bounaadja, M. Schmitt, S. Albrecht, et al., Malar. J. 16 (2017) 382. doi: 10.1186/s12936-017-2032-4
22. [22]
  G. Velmourougane, M.B. Harbut, S. Dalal, et al., J. Med. Chem. 54 (2011) 1655-1666. doi: 10.1021/jm101227t
23. [23]
  C. Ma, J. Cao, X. Liang, et al., Eur. J. Med. Chem. 108 (2016) 21-27. doi: 10.1016/j.ejmech.2015.11.021
24. [24]
  C. Ma, K. Jin, J. Cao, et al., Bioorg. Med. Chem. 21 (2013) 1621-1627. doi: 10.1016/j.bmc.2013.01.068
1. [1]
  Sajid Hussain , Omer M.A. Dagah , Essam A.M.S Obaid , Peng Jin , Ovas Ahmed Dar , Muhammd Irfan , Yiming Qi , Qinghua Wu , Ming Jin , Tengli Zhang , Lei Luo . Chitosan as oral absorption enhancer and inhibitor: A comprehensive review. Chinese Chemical Letters, 2026, 37(1): 111273-. doi: 10.1016/j.cclet.2025.111273
2. [2]
  Anqi Shi , Jiahao Xiang , Qingyun Zhang , Minghui Tan , Wen Xiao , Yang Yang , Lin Zhao , Jian Liu , An Pan , Junwei Wang , Lihong Hu . Discovery of a novel cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy. Chinese Chemical Letters, 2026, 37(8): 111786-. doi: 10.1016/j.cclet.2025.111786
3. [3]
  Yiran Tao , Chunlei Dai , Zhaoxiang Xie , Xinru You , Kaiwen Li , Jun Wu , Hai Huang . Redox responsive polymeric nanoparticles enhance the efficacy of cyclin dependent kinase 7 inhibitor for enhanced treatment of prostate cancer. Chinese Chemical Letters, 2024, 35(8): 109170-. doi: 10.1016/j.cclet.2023.109170
4. [4]
  Jia Chen , Yun Liu , Zerong Long , Yan Li , Hongdeng Qiu . Colorimetric detection of α-glucosidase activity using Ni-CeO₂ nanorods and its application to potential natural inhibitor screening. Chinese Chemical Letters, 2024, 35(9): 109463-. doi: 10.1016/j.cclet.2023.109463
5. [5]
  Chao Chen , Wenwen Yu , Guangen Huang , Xuelian Ren , Xiangli Chen , Yixin Li , Shenggui Liang , Mengmeng Xu , Mingyue Zheng , Yaxi Yang , He Huang , Wei Tang , Bing Zhou . Asymmetric macrocyclization enabled by Rh(Ⅲ)-catalyzed CH activation: Enantioenriched macrocyclic inhibitor of Zika virus infection. Chinese Chemical Letters, 2024, 35(11): 109574-. doi: 10.1016/j.cclet.2024.109574
6. [6]
  Shuheng Zhang , Yuanyuan Zhang , Wanyu Wang , Yuzhu Hu , Xinchuan Chen , Bilan Wang , Xiang Gao . A combination strategy of DOX and VEGFR-2 targeted inhibitor based on nanomicelle for enhancing lymphoma therapy. Chinese Chemical Letters, 2024, 35(12): 109658-. doi: 10.1016/j.cclet.2024.109658
7. [7]
  Zhexin Chen , Yuqing Shi , Fang Zhong , Kai Zhang , Furong Zhang , Shenghong Xie , Zhongbin Cheng , Qian Zhou , Yi-You Huang , Hai-Bin Luo . Discovery of amentoflavone as a natural PDE4 inhibitor with anti-fibrotic effects. Chinese Chemical Letters, 2025, 36(4): 109956-. doi: 10.1016/j.cclet.2024.109956
8. [8]
  Chanqi Ye , Jia Zhang , Jie Shen , Ruyin Chen , Qiong Li , Peng Zhao , Dong Chen , Jian Ruan . Attractive Pickering emulsion gel loaded with oxaliplatin and lactate dehydrogenase inhibitor increases the anti-tumor effect in hepatocellular carcinoma. Chinese Chemical Letters, 2025, 36(7): 110519-. doi: 10.1016/j.cclet.2024.110519
9. [9]
  Wenchao Chen , Xiaoting Niu , Xinyu Liang , Guanghao Zhu , Xue Zhang , Qing Gong , Cen Xie , Guangbo Ge , Ping Wang , Yuqi He . Rationally engineered a universal far-red fluorogenic substrate of bile salt hydrolase for functional imaging and inhibitor screening. Chinese Chemical Letters, 2026, 37(4): 111320-. doi: 10.1016/j.cclet.2025.111320
10. [10]
  Jisheng Liu , Junli Chen , Xifeng Zhang , Yin Wu , Xin Qi , Jie Wang , Xiang Gao . Red blood cell membrane-coated FLT3 inhibitor nanoparticles to enhance FLT3-ITD acute myeloid leukemia treatment. Chinese Chemical Letters, 2024, 35(9): 109779-. doi: 10.1016/j.cclet.2024.109779
11. [11]
  Hui Lei , Yingying Jiang , Jiayu Liu , Weifeng Zhang , Fanbo Meng , Jun Mou , Wenyi Liu , Pengcheng Lei , Rui Xiong , Zan Xu , Hang Zhang , Yanjun Wang , Guo-Bo Li , Lingling Yang , Hua-Li Wang . Structure-activity relationship studies of 3,4-disubstitued indole-2-ketone derivatives identify a potent glutaminyl cyclase inhibitor with antitumor activity against breast cancer. Chinese Chemical Letters, 2026, 37(6): 111511-. doi: 10.1016/j.cclet.2025.111511
12. [12]
  Feng Xu , Ziqi Ning , Donghua Zhang , Chunlong Dai , Qinxue Wen , Fengxia Deng , Bo Lai , Zhiqiang Chen . Mechanism and pathway for the electrocatalytic degradation of an organic phosphine scale inhibitor by a novel Ti/IrO₂-RuO₂(Bi+[Emim]BF₄) electrode. Chinese Chemical Letters, 2026, 37(10): 112435-. doi: 10.1016/j.cclet.2026.112435
13. [13]
  Hejie Zheng , Zhili Wang , Guizhen Luo , Cuicui Du , Xiaohua Zhang , Jinhua Chen . A novel PEC-EC dual-mode biosensing platform for dual target detection of miRNA-133a and cTnI. Chinese Chemical Letters, 2025, 36(4): 110131-. doi: 10.1016/j.cclet.2024.110131
14. [14]
  Zhihui Zhang , Ru Sun , Chong Bian , Hongbo Wang , Zhen Zhao , Panpan Lv , Jianzhong Lu , Haixin Zhang , Hulie Zeng , Yuanyuan Chen , Zhijuan Cao . A dual-protease-triggered chemiluminescent probe for precise tumor imaging. Chinese Chemical Letters, 2025, 36(2): 109784-. doi: 10.1016/j.cclet.2024.109784
15. [15]
  Fei-Yan Gao , Yan Wu , Ling Yang , Zhong-Yi Ma , Yi Chen , Xiao-Man Mao , Xu-Fei Bian , Pei Tang , Chong Li . Orally delivered berberine derivatives for dual therapy in diabetic complications with MRSA infections. Chinese Chemical Letters, 2025, 36(4): 109917-. doi: 10.1016/j.cclet.2024.109917
16. [16]
  Di ZHANG , Tianxiang XIE , Xu HE , Wanyu WEI , Qi FAN , Jie QIAO , Gang JIN , Ningbo LI . Construction and antitumor activity of pH/GSH dual-responsive magnetic nanodrug. Chinese Journal of Inorganic Chemistry, 2025, 41(4): 786-796. doi: 10.11862/CJIC.20240329
17. [17]
  Rui TIAN , Duo LI , Yuan REN , Jiamin CHAI , Xuehua SUN , Haoyu LI , Yuecheng ZHANG . Dual-ligand-modified copper nanoclusters: Synthesis and application in ornidazole detection. Chinese Journal of Inorganic Chemistry, 2025, 41(6): 1245-1255. doi: 10.11862/CJIC.20240389
18. [18]
  Tan Zhang , Zhikai Che , Yuru Song , Jinping Li , Yuhan Sun , Guang Liu . Reinforced nitrogen fixation via synergistic Ru-Ni dual sites. Chinese Chemical Letters, 2025, 36(9): 111295-. doi: 10.1016/j.cclet.2025.111295
19. [19]
  Qian Pang , Fangjun Huo , Yongkang Yue , Caixia Yin . ONOO⁻ and viscosity dual-response fluorescent probe for arthritis imaging in vivo. Chinese Chemical Letters, 2025, 36(9): 110713-. doi: 10.1016/j.cclet.2024.110713
20. [20]
  Pengfei Wu , Chang Sun , Xiao Huang , Wenjing Nie , Qiongqiong Wan , Qingtao Meng , Suming Chen . Dual-identification strategy for global profiling of protein fatty acylation sites. Chinese Chemical Letters, 2026, 37(10): 112530-. doi: 10.1016/j.cclet.2026.112530

Get Citation

PDF

XML

Metrics

PDF Downloads(13)
Abstract views(2822)
HTML views(178)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142