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Identification of Antimalarial targets of chloroquine by a combined deconvolution strategy of ABPP and MS-CETSA

Military Medical Research 2023年第1期10卷 64-77页

作者： Peng Gao Yan-Qing Liu Wei Xiao Fei Xia Jia-Yun Chen Li-Wei Gu Fan Yang Liu-Hai Zheng Jun-Zhe Zhang Qian Zhang Zhi-Jie Li Yu-Qing Meng Yong-Ping Zhu Huan Tang Qiao-Li Shi Qiu-Yan Guo Ying Zhang Cheng-Chao Xu Ling-Yun Dai Ji-Gang Wang Artemisinin Research Center Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing 100700China Department of Traditional Chinese Medicine Southern Medical UniversityGuangzhou 510515China Department of Geriatrics the Second Clinical Medical College of Jinan Universitythe First Affiliated Hospital of Southern University of Science and TechnologyShenzhen People’s HospitalShenzhen 518020GuangdongChina Institute of Molecular and Cell Biology Agency for ScienceTechnology and Research(A*STAR)Singapore 138673Singapore Department of Biological Sciences National University of SingaporeSinga‑pore 117543Singapore

Background: Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine(CQ) has played an indispensable role, however, its mechanism of action(MoA) is not fully understood.Methods: We used the principle of photo-affinity labeling and click chemistry-based functionalization in the design of a CQ probe and developed a combined deconvolution strategy of activity-based protein profiling(ABPP) and mass spectrometry-coupled cellular thermal shift assay(MS-CETSA) that identified the protein targets of CQ in an unbiased manner in this study. The interactions between CQ and these identified potential protein hits were confirmed by biophysical and enzymatic assays.Results: We developed a novel clickable, photo-affinity chloroquine analog probe(CQP) which retains the Antimalarial activity in the nanomole range, and identified a total of 40 proteins that specifically interacted and photocrosslinked with CQP which was inhibited in the presence of excess CQ. Using MS-CETSA, we identified 83 candidate interacting proteins out of a total of 3375 measured parasite proteins. At the same time, we identified 8 proteins as the most potential hits which were commonly identified by both methods.Conclusions: We found that CQ could disrupt glycolysis and energy metabolism of malarial parasites through direct binding with some of the key enzymes, a new mechanism that is different from its well-known inhibitory effect of hemozoin formation. This is the first report of identifying CQ Antimalarial targets by a parallel usage of labeled(ABPP)and label-free(MS-CETSA) methods.

关键词： Chloroquine Antimalaria Activity-based protein profiling(ABPP) Cellular thermal shift assay(CETSA) Quantitative proteomics

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

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Chinese Chemical Letters 2022年第5期33卷 2550-2554页

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 Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJi’nan 250012China Department Applied Biology CSIR-Indian Institute of Chemical TechnologyTarnakaHyderabadTelangana-500007India Academy of Scientific and Innovative Research(AcSIR) Ghaziabad-201002India CSIR-Centre for Cellular and Molecular Biology TarnakaHyderabadTelangana-500007India

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

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通过鉴定关键靶标蛋白探究青蒿素抗疟机制

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Engineering 2023年第12期31卷 86-97页

作者： Peng Gao Jianyou Wang Jiayun Chen Liwei Gu Chen Wang Liting Xu Yin Kwan Wong Huimin Zhang Chengchao Xu Lingyun Dai Jigang Wang State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Artemisinin Research Centerand Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing 100700China Pharmaceutical College Henan UniversityKaifeng 475004China Shandong Academy of Chinese Medicine Jinan 250014China Department of Infectious Disease Shenzhen Clinical Research Centre for GeriatricsShenzhen People’s Hospital&the First Affiliated Hospital of Southern University of Science and TechnologyShenzhen 518020China

The widespread use of artemisinin(ART)and its derivatives has significantly reduced the global burden of malaria;however,malaria still poses a serious threat to global health.Although significant progress has been achieved in elucidating the Antimalarial mechanisms of ART,the most crucial target proteins and pathways of ART remain unknown.Knowledge on the exact Antimalarial mechanisms of ART is urgently needed,as signs of emerging ART resistance have been observed in some regions of the world.Here,we used a combined strategy involving mass spectrometry-coupled cellular thermal shift assay(MS-CETSA)and transcriptomics profiling to identify a group of putative Antimalarial targets of ART.We then conducted a series of validation experiments on five prospective protein targets,demonstrating that ART may function against malaria parasites by interfering with redox homeostasis,lipid metabolism,and protein synthesis processes.Taken together,this study provides fresh perspectives on the Antimalarial mechanisms of ART and identifies several crucial proteins involved in parasite survival that can be targeted to combat malaria.

关键词： Artemisinin Antimalaria Target identification MS-CETSA Transcriptomics

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Antimalarial potential of kolaviron,a biflavonoid from Garcinia kola seeds,against Plasmodium berghei infection in Swiss albino mice

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Asian Pacific Journal of Tropical Medicine 2014年第2期7卷 97-104页

作者： Adaramoyc Oluwatosin Akinpelu Tolulope Kosoko Ayokulchin Okoric Patricia Kehinde Aderemi Falade Catherine Ademowo Olusegun Biochemistry Department University of IbadanUniversity wayOyo-OjooRoadIbadanIbadan.Oyo/South-West 20005Nigeria Pharmacology Department University of IbadanUniversity way.Oyo-OjooRoadIbadanIbadanOyo/South-West 20005Nigeria Medical Microbiology Department.University of Ibadan University wayOyo-OjooRoadIbadanIbadanOyo/South-West 20005Nigeria Pharmacology and IAMRAT Department.University of Ibadan University wayOyo-OjooRoad.IbadanIbadanOyo/South-West 20005.Nigeria

Objective:To investigate the Antimalarial potential of kolaviron(KV),a biflavonoid fraction from Garcinia kola seeds,against Plasmodium berghei(P.berghei)infection in Swiss albino mice.Methods:The study consists of seven groups of ten mice each.Groups I,II and III were normal mice that received com oil.KV1 and chloroquine(CQ),respectively.Groups IV,V,ⅥandⅦwere infected mice that received corn oil.CQ,KYI and KV2.respectively.CQ.KY1 and KV2were given at 10-,100-and 200-mg/kg daily,respectively for three consecutive days.Results:Administration of KV1 and KV2 significantly(PAntimalarial activities in P.berghei-infected mice,in addition to its known antioxidant properties.

关键词： Antimalaria Antioxidant Biflavonoid Kolaviron Plasmodium berghei

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Effect of artemether on hematological parameters of healthy and uninfected adult Wistar rats

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Asian Pacific Journal of Tropical Biomedicine 2012年第6期2卷 493-495页

作者： Osonuga IO Osonuga OA Osonuga A Onadeko AA Osonuga AA Department of Physiology Olabisi Onabanjo University Department of Pharmacology Olabisi Onabanjo University School of Medical Sciences University of Cape Coast Department of Nursing University of Cape Coast

Objective:To evaluate the effect of short term artemether administration on some blood parameters in adult male Wistar rats.Methods:Sixty five albino rats with body weight of 190-220 g were used for the four-phased study. The animals were randomly divided into five groups. The first-four groups of 15 rats were further divided into 3 subgroups of 5 rats. The drug was administered orally at sub-optimal, therapeutic, and high doses of 25, 50 and 75 mg/kg bw,respectively to the rats for 1 day, 2 days and 3 days. Blood samples were collected by cardio-puncture from the rats for hematology at the end of each phase. The last group served as control,and they were given waterad libitum.Results:Artemether caused significant reduction(P<0.05)of the hematological profile of the animals in a dose dependent manner. Discontinuation of the drug use however showed gradual recovery of the depressed indices of the blood parameters.Conclusions:The results suggest that artemether can induce reversible changes in hematological profiles of rats by extension man. This can probably aggravate anemia when artemether is administered to malaria patients. Hence, the study supports the use of the drug with cautione specially in patients prone to anemic tendencies.

关键词： Artemether Anemia Antimalaria Hematology Hematological profile Malaria Anemic tendency

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A comparative laboratory diagnosis of malaria:microscopy versus rapid diagnostic test kits

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Asian Pacific Journal of Tropical Biomedicine 2012年第4期2卷 307-310页

作者： Azikiwe CCA Ifezulike CC Siminialayi IM Amazu LU Enye JC Nwakwunite OE Department of Pharmacology Anambra State University Department of Pharmacology University of Port Harcourt Department of Immunology/Parasitology Madonna University

Objective:To compare the two methods of rapid diagnostic tests(RDTs)and microscopy in the diagnosis of malaria.Methods:RDTs and microscopy were carried out to diagnose malaria. Percentage malaria parasitaemia was calculated on thin films and all non-acute cases of plasmodiasis with less than 0.001%malaria parasitaemia were regarded as negative.Results were simply presented as percentage positive of the total number of patients under study.The results of RDTs were compared to those of microscopy while those of RDTs based on antigen were compared to those of RDTs based on antibody.Patients' follow-up was made for all cases.Results: All the 200 patients under present study tested positive to RDTs based on malaria antibodies(serum)method(100%).128 out of 200 tested positive to RDTs based on malaria antigen(whole blood)method(64%),while 118 out of 200 patients under present study tested positive to visual microscopy of Lieshman and diluted Giemsa(59%).All patients that tested positive to microscopy also tested positive to RDTs based on antigen.All patients on the second day of follow-up were non-febrile and had Antimalaria drugs.Conclusions;We conclude based on the present study that the RDTs based on malaria antigen(whole blood)method is as specific as the traditional microscopy and even appears more sensitive than microscopy.The RDTs based on antibody(serum)method is unspecific thus it should not be encouraged.It is most likely that Africa being an endemic region,formation of certain levels of malaria antibody may not be uncommon.The present study also supports the opinion that a good number of febrile cases is not due to malaria. We support WHO's report on cost effectiveness of RDTs but,recommend that only the antigen based method should possibly,be adopted in Africa and other malaria endemic regions of the world.

关键词： Rapid diagnostic tests Microscopy Malaria diagnosis Malaria Parasitaemia Plasmodiasis Antigen Antibody Antimalaria Serum Whole blood

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A review of age-old Antimalarial drug to combat malaria:efficacy upgradation by nanotechnology based drug delivery

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Asian Pacific Journal of Tropical Medicine 2014年第9期7卷 673-679页

作者： Satyajit Tripathy Somenath Roy Immunology and Microbiology Laboratory Department of Human Physiology with Community HealthVidyasagar UniversityMidnapore-721102West BengalIndia

Malaria is uncontrolled burden in the world till now.Despite of different efforts to develop Antimalarial drug for decades,any anti-malarial drug can able to eradicate completely till now.Many anti-malarial substances are practically ineffectual because of their physicochemical limitations,cytotoxicity,chemical instability and degradation,and limited activities against intracellular parasites.Taking into consideration,the amount of research is going to conduct in the field of nanoparticle based drug delivery systems,lead to new ways of improving the treatment of infectious diseases.The study has focused on the progress and advancement of research on nanotechnology based drug delivery to eradicate the malaria.We like to focus the efficacy of nanotechnology based drug application for the opening out of novel chemotherapeutics in laboratory research,which may show the way to better use with age-old Antimalarial drug and may draw the attention of pharmaceutical industries for the improvement and designing of effective anti-malarial drugs in future.

关键词： Nanotechnology Age-old drug Drug efficacy Antimalaria Nanomedicine

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Oral Amodiaquine, Artesunate and Artesunate Amodiaquine Combination Affects Open Field Behaviors and Spatial Memory in Healthy Swiss Mice

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Journal of Behavioral and Brain Science 2013年第8期3卷 569-575页

作者： Adejoke Yetunde Onaolapo Olakunle James Onaolapo Emmanuel O. Awe Samuel Oloyede Ayomide Joel Department of Human Anatomy Faculty of Basic Medical Sciences College of Health Sciences Ladoke Akintola University Ogbomoso Nigeria Department of Pharmacology Faculty of Basic Medical Sciences College of Health Sciences Ladoke Akintola University Oshogbo Nigeria

Effects of amodiaquine, artesunate and artesunate amodiaquine combination on open field novelty-induced behaviors and spatial memory in healthy mice were studied. Forty mice were used in the open field and fifty each in the radial arm maze and Y maze;mice were assigned into four or five groups of ten each, Group A served as control (distilled water), Groups B, C and D received artesunate (4 mg/kg), amodiaquine (10 mg/kg) and artesunate-amodiaquine combination (4 mg/kg and10 mg/kg) respectively, while Group E animals (for the cognition tests) were given scopolamine (2 mg/kg). Drugs and vehicle were administered orally for three days. Results were analysed by one way analysis of variance followed by a posthoc test. Results showed that artesunate and amodiaquine either in combination or administered singly caused a significant increase in open field novelty-induced horizontal locomotion and rearing. Grooming in the open field showed increments in the artesunate alone and artesunate amodiaquine groups while significant reductions in spatial memory were also seen in the cognition models used.

关键词： Neurobehavior Artesunate Amodiaquine Antimalaria Novelty-Induced Behaviors Cognition

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A combination of the leaves and tuber of Icacina senegalensis A.Juss(Icacinaceae)improves the Antimalarial activity of the plant in mice

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Journal of Coastal Life Medicine 2015年第10期3卷 821-825页

作者： Esien David-Oku Juliet Ifeoma Obiajunwa-Otteh Biochemistry Department Faculty of Basic Medical SciencesUniversity of CalabarCalabarNigeria

Objective:To investigate the possibility of increased Antimalarial activity of Icacina senegalensis A.Juss(Icacinaceae)upon a combination of its leaves and tubers against Plasmodium berghei malaria in mice.Methods:Chloroquine sensitive ANKA clones of Plasmodium berghei were used to develop experimental models based on intraperitoneal injection of 10^(7)parasitized erythrocytes in phosphate buffer saline(pH 7.2)and subsequent development of parasitemia.The models were employed to investigate prophylactic and curative anti-malarial activities of tuber and tuberleaf methanol extracts of the plant at selected dosages(25,50 and 100 mg/kg body weight).Chloroquine with a curative dosage of 10 mg/kg body weight was used as positive control in both studies.Results:Tuber and tuber-leaf extracts produced a dose-dependent chemosuppression of the parasites,with higher activity and mean survival time exhibited by the combined extract.Conclusions:Anti-plasmodia activity has been discovered in methanol extract of Icacina senegalensis tuber extract.The observed optimization of the Antimalarial actions of the plant upon a combination of its leaf and tuber opens a new area of medicinal plant research.

关键词： Icacina senegalensis tuber Antimalaria Mice Plasmodium berghei Chemosuppression Curative

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Chemical Compositions of <i>Lonchocarpus cyanescens</i>Benth., (Fabaceae)—Case Study of Its Volatile Oils, and Two Triterpenoids

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American Journal of Plant Sciences 2013年第8期4卷 1653-1659页

作者： Dorcas Olufunke Moronkola Ibrahim Adebayo Oladosu Department of Chemistry University of Ibadan Ibadan Nigeria.

Leaf and stem essential oils of Lonchocarpus cyanescens Benth., (Fabaceae) were obtained by hydro-distillation, using all-glass apparatus adapted to British Pharmacopeia specifications with yields of 0.03% and 0.17% respectively. The oils were investigated by GC and GC-MS analyses. Results show seven compounds were responsible for 90.4% of leaf;eleven compounds responsible for 97.6% of stem volatile oils. Phytol (62.5%) and hexadecanoic acid (12.4%) dominate the leaf oil;octadecenoic (24.1%) and hexadecanoic acids (17.2%) are predominant in the stem oil. Phytochemical screening of stem, leaf, and root methanol extracts of Lonchocarpus cyanescens reveal presence of following seven classes of metabolites: saponin, tannin, steroid, terpenoid, cardiac glycosides, phlobatannins and flavonoids. Partitioning of methanol extract from dried leaf of it with ethylacetate gave fraction, which was chromatographed using gradient elution. TLC with high Rf was used in monitoring elution. Two white crystalline solids eluted at 5% and 10% ethylethanoate in hexane, were re-crystallized and characterized. They were subjected to Infra-Red spectra, mass spectrometry (ESI technique), 1H and 13C-NMR analyses, which confirmed they are triterpenoids. Above mentioned metabolites may be responsible for literature acclaimed bio-activities L. cyanescens display [anti-inflammatory, anti-arthritic, anti-microbial effects]. This paper presents details of above results which are new in literature.

关键词： Lonchocarpus cyanescens Fabaceae Antimalaria Phytochemistry Essential Oils GC GC-MS HPLC IR 1H and 13C-NMR

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