Novel antimalarial drug targets: hope for new antimalarial drugs

Malaria is a major global threat, that results in more than 2 million deaths each year. The treatment of malaria is becoming extremely difficult due to the emergence of drug-resistant parasites, the absence of an effective vaccine, and the spread of insecticide-resistant vectors. Thus, malarial therapy needs new chemotherapeutic approaches leading to the search for new drug targets. Here, we discuss different approaches to identifying novel antimalarial drug targets. We have also given due attention to the existing validated targets with a view to develop novel, rationally designed lead molecules. Some of the important parasite proteins are claimed to be the targets; however, further in vitro or in vivo structure–function studies of such proteins are crucial to validate these proteins as suitable targets. The interactome analysis among apicoplast, mitochondrion and genomic DNA will also be useful in identifying vital pathways or proteins regulating critical pathways for parasite growth and survival, and could be attractive targets. Molecules responsible for parasite invasion to host erythrocytes and ion channels of infected erythrocytes, essential for intra-erythrocyte survival and stage progression of parasites are also becoming attractive targets. This review will discuss and highlight the current understanding regarding the potential antimalarial drug targets, which could be utilized to develop novel antimalarials.     

Methnaridine is an orally bioavailable,fast‐killing and long‐acting antimalarial agent that cures Plasmodium infections in mice

Background and PurposeMalaria is one of the deadliest diseases in the world. Novel chemotherapeutic agents are urgently required to combat the widespread Plasmodium resistance to frontline drugs. Here, we report the discovery of a novel benzonaphthyridine antimalarial, methnaridine, which was identified using a structural optimization strategy.Experimental ApproachAn integrated pharmacological approach was used to evaluate the antimalarial profile of methnaridine. The pharmacokinetic properties of methnaridine were investigated along with the associated safety profile. Host immune response patterns were also analysed.Key ResultsMethnaridine exhibited potent antimalarial activity against P. falciparum (3D7: IC₅₀ = 0.0066 μM; Dd2: IC₅₀ = 0.0056 μM). In P. berghei‐infected mice, oral administration effectively suppressed parasitemia (ED₅₀ = 0.52 mg·kg⁻¹·day⁻¹) and cured the established infection (CD₅₀ = 10.13 mg·kg⁻¹·day⁻¹). These results are equivalent to or better than those of other antimalarial agents in clinical use. Notably, a four‐dose oral regimen at a dosage of 25 mg·kg⁻¹ achieved a complete cure of P. berghei infection in mice. Methnaridine exhibited a rapid parasiticidal profile (PCT₉₉ = 36.0 h) and showed no cross‐resistance to chloroquine. Pharmacokinetic studies revealed that methnaridine is readily absorbed, long‐lasting and slowly cleared. The safety profile of methnaridine is also satisfactory (maximum tolerated dose = 1,125 mg·kg⁻¹). In addition, following methnaridine treatment, infection‐induced Th1 immune response was almost fully alleviated in mice.Conclusion and ImplicationsMethnaridine is an orally bioavailable, fast‐acting and long‐lasting agent with excellent antimalarial properties. Our study highlights the potential of methnaridine for clinical development as a promising antimalarial candidate.     

AQ-13 - an investigational antimalarial drug

Introduction: AQ-13 is a drug candidate in development for the treatment of Plasmodium falciparum infections. The chemical structure is similar to chloroquine, a 4-aminoquinoline, with a shorter diaminoalkane side chain. Chloroquine has been the standard of care for P.falciparum malaria for more than 40 years, but the spread of resistant parasites in all malaria endemic regions has led to abandonment of the drug. The outstanding attribute of AQ-13 is its retrieval of activity against chloroquine-resistant P.falciparum.

Areas covered: We review preclinical and clinical studies on AQ-13 and summarize findings on pharmacokinetic, safety, potency and efficacy.

Expert opinion: Based on its properties invivo, the most likely future indication of AQ-13 could be case management of uncomplicated falciparum malaria – as a partner drug in a combination therapy. Several 4-aminoquinolines combined with a partner drug are on the market and in development. The outstanding properties of AQ-13 should be identified to direct further clinical development.     

Evaluation of herbal antimalarial MAMA decoction-amodiaquine combination in murine malaria model

Context: Co-administration of amodiaquine with MAMA decoction (MD), an herbal antimalarial drug comprising the leaves of Mangifera indica L. (Anacardiaceae), Alstonia boonei De Wild (Apocynaceae), Morinda lucida Benth (Rubiaceae) and Azadirachta indica A. Juss (Meliaceae) was investigated. The practice of concurrent administration of herbal medicines with orthodox drugs is currently on the increase globally.

Objective: The study was designed to investigate the possible enhancement of the antimalarial potency as well as possible herb–drug interaction resulting from concurrent administration of MAMA decoction with amodiaquine (AQ).

Materials and methods: Combinations of MD with AQ were investigated in chloroquine (CQ)-sensitive Plasmodium berghei NK 65 in varying oral doses (mg/kg) at: sub-therapeutic [MD30?+?AQ1.25], therapeutic [MD120?+?AQ10] and median effective [MD40?+?AQ3.8], using chemosuppressive and curative antimalarial test models. Secondly, P. berghei ANKA (CQ-resistant)-infected mice were orally treated with MD 120, 240, [MD120?+?AQ10] and [MD240?+?AQ10] mg/kg, using both models. The survival times of mice were monitored for 28 d.

Results: ED₅₀ values of MD and AQ were 48.8 and 4.1?mg/kg, respectively. A total parasite clearance of CQ-sensitive P. berghei NK65 was obtained with the therapeutic combination dose in the curative test giving an enhanced survival time. In CQ-resistant P. berghei ANKA-infected mice, [MD120?+?AQ10] and [MD240?+?AQ10] mg/kg gave comparable activities with AQ (10?mg/kg) in both models.

Conclusion: The therapeutic combination dose gave total parasite clearance of CQ-sensitive P. berghei NK65, whereas none of the doses tested showed notable activity against CQ-resistant P. berghei ANKA.     

微生物基因组上药物作用靶位的识别

在基因组时代 ,开发抗微生物的新药离不开基因组研究 ,基因组测序和生物信息学的迅猛发展使得微生物基因组上药物作用靶位的识别成为可能 ,并将使得细菌、真菌和寄生虫等对抗生素的耐药性成为过去。本文综述了应用基因组信息技术识别微生物基因组上药物作用靶位的方法和进展     

Novel molecular targets for the therapy of urothelial carcinoma

Introduction: First-line platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma; however, long-term outcomes including disease-specific and overall survival remain suboptimal. In addition, approximately 40 – 50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy. Improvements in our understanding of the molecular mechanisms of urothelial tumorigenesis have led to first-generation clinical trials evaluating novel agents targeting molecular pathways. These are particularly relevant in regard to subpopulations. Novel trial designs warrant consideration to accelerate accrual.

Areas covered: In this review, novel molecular targets for the therapy of urothelial carcinoma, as well as recently completed and ongoing clinical trials utilizing novel targeted agents, are discussed. A Medline search with key words, abstracts reported at national conferences on urothelial carcinoma and NCI clinical trial identifiers was used for this review.

Expert opinion: Improved understanding of molecular biology has identified a number of new molecular targets, but there is a seeming absence of one dominant molecular driver for urothelial cancer. An adaptive and biomarker-derived strategy may be warranted. Clinical trials utilizing targeted agents are ongoing and results are awaited.     

Antimalarial drug discovery: screening of Brazilian medicinal plants and purified compounds

Background: Malaria is the most important parasitic disease and its control depends on specific chemotherapy, now complicated by Plasmodium falciparum that has become resistant to most commonly available antimalarials. Treatment of the disease requires quinine or drug combinations of artemisinin derivatives and other antimalarials. Further drug resistance is expected. New active compounds need to be discovered. Objective/method: To find new antimalarials from medicinal and randomly collected plants, crude extracts are screened against P. falciparum in cultures and in malaria animal models, following bioassays of purified fractions, and cytotoxicity tests. Conclusion: For antimalarial research, screening medicinal plants is more efficient than screening randomly chosen plants. Biomonitored fractionation allows selection of new active molecules identified as potential antimalarials in multidisciplinary projects in Brazil; no new molecule is available for human testing. The advantages of projects based on ethnopharmacology are discussed.     

抗艾滋病药物研究的新靶点

目前,临床使用的抗艾滋病药物主要是逆转录酶抑制剂和蛋白酶抑制剂。由于这些药物的毒性和耐药性等问题日益严重,寻找抗艾滋病药物的新靶点已经成为当务之急。在细胞水平上对HIV病毒自身生活周期的研究发现了一些新的药物靶点,其中包括病毒自身生活周期所需的蛋白,宿主细胞内源性抗病毒因子及其他抗HIV-1感染的潜在靶标。本文对近年来研究中出现的新的抗艾滋病药物靶点作一综述。     

In search of novel protein drug targets for treatment of Enterococcus faecalis infections

Enterococcus faecalis (Ef) is one of the major pathogens involved in hospital‐acquired infections. It can cause nosocomial bacteremia, surgical wound infection, and urinary tract infection. It is important to mention here that Ef is developing resistance against many commonly occurring antibiotics. The occurrence of multidrug resistance (MDR) and extensive‐drug resistance (XDR) is now posing a major challenge to the medical community. In this regard, to combat the infections caused by Ef, we have to look for an alternative. Rational structure‐based drug design exploits the three‐dimensional structure of the target protein, which can be unraveled by various techniques such as X‐ray crystallography or nuclear magnetic resonance (NMR) spectroscopy. In this review, we have discussed the complete picture of Ef infections, the possible treatment available at present, and the alternative treatment options to be explored. This study will help in better understanding of novel biological targets against Ef and the compounds, which are likely to bind with these targets. Using these detailed structural informations, rational structure‐based drug design is achievable and tight inhibitors against Ef can be prepared.     

Benzoxaborole antimalarial agents. Part 3: design and syntheses of (carboxy‐13C‐3,3‐2H2)‐labeled and (3‐14C)‐labeled 7‐(2‐carboxyethyl)‐1,3‐dihydro‐1‐hydroxy‐2,1‐benzoxaboroles

Two new isotopically labeled compounds, (carboxy‐¹³C‐3,3‐²H₂)‐7‐(2‐carboxyethyl)‐1,3‐dihydro‐1‐hydroxy‐2,1‐benzoxaborole (2) and (3‐¹⁴C)‐7‐(2‐carboxyethyl)‐1,3‐dihydro‐1‐hydroxy‐2,1‐benzoxaborole (3), were designed and synthesized to support the preclinical development studies of a potential new antimalarial agent, 7‐(2‐carboxyethyl)‐1,3‐dihydro‐1‐hydroxy‐2,1‐benzoxaborole (1). Copyright © 2012 John Wiley & Sons, Ltd.     

Antiplasmodial drug targets: a patent review (2000 – 2013)

Introduction: New antimalarials with novel modes of action are crucial in countering the challenge of emerging drug-resistant Plasmodium falciparum. Equally significant is the identification and characterization of the targets these compounds inhibit. Biochemical evidence from seminal studies, whole genome clues and high-throughput chemical screening data provide starting points worth exploring in target identification efforts. Several proteins and biochemical processes/pathways critical to parasite survival have since been profiled and patented.

Areas covered: In this review, an analysis of patents describing the characterization of different enzymatic and/or biosynthetic targets in P. falciparum over the last fourteen years is presented. The review also details structures, biological evaluation, potential modes of action and therapeutic utilities of small molecule antiplasmodial compounds from ongoing research, designed to inhibit these targets.

Expert opinion: Though various strategies to address antimalarial drug resistance exist, direct inhibition of unrelated targets and non-genome coded processes potentially present the most effective options. Additionally, interest in peptides as antimalarials merits further exploration especially in view of their unique low susceptibility to resistance, wider spectrum of action and faster activity. Finally, target-based optimization and chemical validation of novel targets can be facilitated by routine phenotypic whole-cell screening of antiplasmodial hits against any new target(s).     

Plasmodium and host lactate dehydrogenase molecular function and biological pathways: implication for antimalarial drug discovery

Lactate dehydrogenase is an enzyme that catalyses the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD(+). Lactate dehydrogenase is present at high levels in humans and Plasmodium spp. However, the function of lactate dehydrogenase in malarial infection is not well characterized. In this investigation, a new gene ontology technology is used to predict molecular function and biological pathways of lactate dehydrogenase. In comparison with human lactate dehydrogenase, the P. falciparum lactate dehydrogenase has similar molecular functions such as L-lactate dehydrogenase activity. Furthermore, P. falciparum lactate dehydrogenase has L-malate dehydrogenase activity. Although the amino acid sequences for human and P. falciparum lactate dehydrogenase are very different, the molecular functions are similar. This suggests that any non-selective therapeutic treatment aimed at blocking P. falciparum lactate dehydrogenase function may affect human lactate dehydrogenase. In contrast, a selective lactate dehydrogenase inhibitor targeting the l-malate dehydrogenase function of P. falciparum and its corresponding tricarboxylic acid cycle provides an attractive therapeutic opportunity.     

药物靶标热点领域的共词聚类分析研究

后基因组时代的药物靶标是创新药物开发的源泉,了解药物靶标的热点领域有利于针对性地开展创新药物的研究工作.现对2003-2007年MEDLINE数据库收录的药物靶标文献的高频主题词进行共词聚类统计分析,并通过聚类映射图和战略坐标等分析结果与专业知识相结合,揭示药物靶标的热点领域.研究发现,目前的靶标研究主要聚焦在抗肿瘤领域,尤其是酶的药理学研究;结晶学、计算机模拟、生物模型等药靶开发技术也应值得重点关注.     

Synthesis of novel benzimidazole acrylonitriles for inhibition of Plasmodium falciparum growth by dual target inhibition

Antimalarial drug resistance has emerged as a threat for treating malaria, generating a need to design and develop newer, more efficient antimalarial agents. This research aimed to identify novel leads as antimalarials. Dual receptor mechanism could be a good strategy to combat developing drug resistance. A series of benzimidazole acrylonitriles containing 18 compounds were designed, synthesized and evaluated for cytotoxicity, heme binding, ferriprotoporphyrin IX biomineralisation inhibition, and falcipain‐2 enzyme assay. Furthermore, in silico docking and MD simulation studies were also performed.The tests revealed quite encouraging results. Three compounds, viz. R‐01 (0.69 μM), R‐04 (1.60 μM), and R‐08 (1.61 μM), were found to have high antimalarial activity. These compounds were found to be in bearable cytotoxicity limits and their biological assay suggested that they had inhibitory activity against falcipain‐2 and hemozoin formation. The docking revealed the binding mode of benzimidazole acrylonitrile derivatives and MD simulation studies revealed that the protein‐ligand complex was stable. The agents exhibit good hemozoin formation inhibition activity and, hence, may be utilized as leads to design a newer drug class to overcome the drug resistance of hemozoin formation inhibitors such as chloroquine.     

Humanized mouse models infected with human Plasmodium species for antimalarial drug discovery

Introduction: Efforts on malaria drug discovery are expected to increase in the coming years to achieve malaria eradication. Owing to the increasing number of new potential candidates together with the actual limitations of the primate models, humanized mouse models infected with human Plasmodium spp. (HmHP) now appear as an alternative to the primate model.

Areas covered: The authors review the progress obtained in the HmHP in the last two decades, with a special emphasis of their input on the drug discovery pathway. The authors discuss the methodologies and strategies used in these models to obtain an accurate assessment of the compound activity and a reliable prediction of the human efficacious regimen.

Expert opinion: Research efforts have led us to an era in which HmHP can successfully be infected with P. falciparum, P vivax and P. ovale. Furthermore, it is now a reality that the complete human cycle of P. falciparum can be obtained in HmHP. The HmHP has shown a real input mainly in the preclinical evaluation of new compounds against the erythrocytic stages of P. falciparum. However, further technical improvements are needed before HmHP may replace the primate model.     

Potential biological targets for bioassay development in drug discovery of Sturge–Weber syndrome

Sturge–Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port‐wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against its progression. Development of such platforms of bioassay can bring along the implementation of high‐throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of molecular targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholinesterase, alkaline phosphatase, GABAergic receptors, Hypoxia‐Inducible Factor (HIF)‐1α and 2α are suggested.     

Synthesis of [2H]‐ and [13C]‐labeled pyronaridine tetraphosphate—an antimalarial drug

The increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and other antimalarial drugs, necessitates the need for developing novel antimalarial drugs with a potent pharmacological activity. Pyronaridine tetraphosphate (PNDP) is one such drug that is currently undergoing preclinical and clinical trials for use in a chemotherapy treatment of malaria. The present investigation was carried out with the objective of synthesizing carbon‐13 [¹³C]‐ and deuterium [²H]‐labeled PNDP for use in studying the ADME and pharmacokinetics of the drug. Here, we present a methodology to synthesize [¹³C]‐ and [²H]‐PNDP using a microwave irradiation technique as this method was found to be more advantageous than the classical method. The labeled compounds thus synthesized had a chemical purity of >99% as determined by HPLC and were also found to be relatively stable up to 3 months when stored under standard conditions. Further they also revealed satisfactory instrumental analysis data. Copyright © 2008 John Wiley & Sons, Ltd.