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.     

Novel molecular targets for antimalarial drug development

Malaria with one million deaths and about 500 million new cases reported annually is a challenge to drug therapy and discovery. As current antimalarial therapeutics become increasingly ineffective because of parasitic resistance, there exists an urgent need to develop and pursue new therapeutic strategies. Antimalarial drug development can follow several strategies, ranging from minor modifications of existing agents to the design of novel agents that act against new targets. Recent advances in our knowledge of parasite biology as well as the availability of the genome sequence provide a wide range of novel targets for drug design. Several promising targets for drug intervention have been revealed in recent years. This review discusses novel molecular targets of the malaria parasite available to the drug discovery scientist.     

New targets, new hope: novel drug targets for curbing malaria

Malaria continues to plague the tropical and subtropical regions causing high morbidity and mortality. Every year, millions die due to lack of affordable and effective anti-malarial drugs. Malaria poses significant threat to half of the world's population and our arsenal to combat this disease is nearly empty. Pharmaceutical companies shy away from investing in research and development for anti-malarial drugs and have shunned it as non-profitable venture. In wake of emergence and spread of drug resistant malaria to newer territories, there is imperative need to develop new drugs for curbing malaria. This underscores the need of exploring new drug targets and reevaluation of existing drug targets. Availability of genome sequence of both parasite and human host has greatly facilitated the search for novel drug targets. This endeavor is complemented well by advances in functional genomics, structure - based drug design and high throughput screening methods and raises much optimism about winning this battle against malaria. This review discusses potential drug targets in the malarial parasite for designing intervention strategies and suitable chemotherapeutic agents.     

Emerging targets for antimalarial drugs

The absence of an effective vaccine against malaria and the ability of the parasite to develop resistance to known antimalarial drugs makes it mandatory to unravel newer drug targets with a view to developing newer pharmacophores. While conventional targets such as the purine, pyrimidine and folate pathways are still being investigated in the light of newer knowledge, a new opportunity has emerged from an understanding of certain unique features of the parasite biology. These include the food vacuole, haemoglobin catabolism, haeme biosynthesis, apicoplasts and their metabolism as well as macromolecular transactions, import of host proteins, parasite induced alterations in the red cell surface and transport phenomena. This review seeks to emphasise the new and emerging targets, while giving a brief account of the targets that have already been exploited.     

Novel molecular targets for antimalarial chemotherapy

The emergence and spread of drug-resistant malaria parasites is a serious public health problem in the tropical world. Malaria control has relied upon the traditional quinoline, antifolate and artemisinin compounds. Very few new antimalarials were developed in the last quarter of the 20th century. An alarming increase in drug-resistant strains of the malaria parasite poses a significant problem for effective control. Recent advances in our knowledge of parasite biology as well as the availability of the genome sequence provide a wide range of novel targets for drug design. Gene products involved in controlling vital aspects of parasite metabolism and organelle function could be attractive targets. It is expected that the application of functional genomic tools in combination with modern approaches such as structure-based drug design and combinatorial chemistry will lead to the development of effective new drugs against drug-resistant malaria strains. This review discusses novel molecular targets of the malaria parasite available to the drug discovery scientist.     

Novel drug targets in malaria parasite with potential to yield antimalarial drugs with long useful therapeutic lives

The status of chemotherapy as the main strategy in malaria control is rapidly being eroded by development of drug resistant Plasmodia, causing malaria to be dubbed a "re-emerging disease". To counter this misfortune, there is an urgent need to develop novel antimalarial drugs capable of delaying resistance, or circumventing it altogether. Mode of action of antimalarial drugs, inter alia, has a bearing on their useful therapeutic lives (UTLs), with single target drugs having short UTLs compared with drugs which possess pleiotropic action. Quinolines and artemisinins are the two classes of drugs with pleiotropic action and subsequently long UTLs. All other antimalarials are single-target drugs, and have been rendered ineffective within 1 to 5 years of their introduction for clinical use. This strongly underlines the need for development of new antimalarial therapies possessing long UTLs. The present review explores novel drug targets within the malaria parasite that may be exploited in the search for novel drugs that possess long and UTLs.     

Antiherpesvirus drugs: a promising spectrum of new drugs and drug targets

In the absence of effective vaccines to control herpesvirus infections, nucleosidic antiviral drugs have been the mainstay of clinical treatment since their development in the late 1970s. However, given the drawbacks of these drugs, including the increasing emergence of drug-resistant clinical isolates, new strategies for treating herpesvirus infections are warranted. A range of promising new drugs with novel molecular targets has been developed, but will they cure latent infections?     

Cyclin-dependent protein kinases as therapeutic drug targets for antimalarial drug development

Cyclin-dependent protein kinases (CDKs) have been attractive drug targets for the development of anticancer therapies due to their direct and crucial role in the regulation of cellular proliferation. Following this trend, CDKs have been pursued as potential drug targets for several other diseases. Structure-based drug design programmes have focused on the plasmodial CDKs to develop new candidate antimalarial compounds. This review discusses the most recent advances relating to three Plasmodium falciparum CDKs (PfPK5, PfPK6 and Pfmrk) as they are developed as antimalarial drug targets. CDKs are highly conserved, and focus must be placed upon the amino acid differences between human and plasmodial CDKs in order to develop specific inhibitors. Comparisons of the active sites of human and parasite CDKs reveal sequence and potential structural variations. Using sequence analysis, molecular modelling and in vitro drug screening, it is possible to identify and develop inhibitors that specifically target the plasmodial CDKs. These efforts are aimed at identifying new classes of CDK inhibitors that may be exploited for antimalarial drug development.     

Novel targets for VEGF-independent anti-angiogenic drugs

INTRODUCTION: In the last decades, the active research in the field of tumor angiogenesis led to the development of a class of agents providing an effective inhibition of neovessels formation through the blockade of VEGF-related pathways. More recently, the identification of several non-VEGF factors such as PDGF, FGF, HGF, angiopoietins, ALK1/endoglin, endothelis and ephrins involved in tumor angiogenesis have emphasized the need to develop agents targeting multiple pro-angiogenic pathways. AREAS COVERED: This review aimed at summarizing the role of non-VEGF molecular pathways in targeting tumor angiogenesis. Preclinical and clinical data for investigational agents against non-VEGF targets have been reviewed emphasizing the role of combined inhibition strategies. EXPERT OPINION: Besides the successful development of drugs providing a specific VEGF blockade, novel agents targeting alternative angiogenesis-related pathways are being tested. Although it seems that the potential clinical usefulness of these novel compounds have been not yet fully investigated, sunitinib, sorafenib, pazopanib and other multikinase inhibitors have certainly displayed encouraging results. A more in-depth clarification of anti-angiogenic agents is still needed, in order to design the best clinical setting and schedule for target-based agents and possibly anticipate potential tools to overcome the emerging issue of anti-angiogenic drug resistance.     

Novel natural vanilloid receptor agonists: new therapeutic targets for drug development.

The discovery that compounds lacking a recognizable vanillyl-like motif might act as vanilloids has given new impetus to a search for novel vanilloid receptor agonists and antagonists in compound libraries. The availability of cell lines transfected with a cloned human vanilloid receptor will further expedite this search. In this article, the pharmacological properties of unsaturated dialdehydes and triprenyl phenols that represent two newly discovered chemical classes of vanilloids will be discussed. The existence of vanilloid receptors in several brain nuclei as well as in non-neuronal tissues predicts novel, innovative therapeutic indications for vanilloids. However, these findings also suggest that vanilloids might cause side-effects. An exploration of the uses of unsaturated dialdehydes in indigenous medicine might help identify new therapeutic targets for vanilloids and avoid unwanted actions.     

Novel approaches in antimalarial drug discovery

Introduction: The development of new antimalarial drugs remains of the utmost importance, since Plasmodium falciparum has developed resistance against nearly all chemotherapeutics in clinical use. In an effort to contain the resistance of P. falciparum against artemisinins and to further eradication efforts, studies are ongoing to identify novel and more efficacious approaches to develop antimalarials.

Areas covered: The authors review the classical and new approaches to antimalarial drug discovery, with a special emphasis on the various stages of the parasite's life cycle and the different Plasmodium species. The authors discuss the methodologies and strategies for early efficacy testing that aim to narrow down the portfolio of promising compounds.

Expert opinion: The increased efforts in the discovery and development of new antimalarial compounds have led to the recognition of new promising hits. However, there is still major roadblock of selecting the most promising compounds and then further testing them in early clinical trials, especially in the current restricted economy. Controlled human malaria infection has much potential for speeding-up the early development process of many drug candidates including those which target the pre-erythrocytic stages.     

Novel approaches to antimalarial drug discovery

Major advances in our understanding of malaria parasite biology have been made. Coupled with the completion of the malaria genome, this has presented exciting opportunities for target-based antimalarial drug discovery. However, the unraveling of more validated biological targets will not necessarily translate into the identification of new chemical entities that are effective against drug resistant parasites in the long term. As history has already shown, development of antiplasmodial agents aimed at a single parasite target or specialized process has failed to stem the tide of drug resistance. This review highlights recent starting points and/or approaches to antimalarial drug discovery with particular emphasis on innovative efforts, which are not necessarily based on the identification of new drug targets and attendant inhibitor design. Approaches covered include utilization of validated chemical scaffolds, bioprecursor and carrier prodrugs, double drug development and/or multi-therapeutic strategies, use of metallocenic scaffolds, the medicinal chemistry of antimalarial natural products and in silico drug design.     

Novel targets for antibiotic drug design

The urgent need for new antibiotics has led to an explosion in the number and diversity of antibiotic drug targets under investigation. The majority of such targets are enzymes required for essential cellular functions. Often, such novel targets are completely unexploited for antibiotic therapy and therefore have the advantage of avoiding current resistance mechanisms. In general, the most advanced novel targets are drawn from processes where an existing antibacterial compound has validated that process for antibiotic therapy. This review describes a number of the more promising targets under development.     

Novel targets for tuberculosis drug discovery

Since the determination of the Mycobacterium tuberculosis genome sequence, various groups have used the genomic information to identify and validate targets as the basis for the development of new anti-tuberculosis agents. Validation might include many components: demonstration of the biochemical activity of the enzyme, determination of its crystal structure in complex with an inhibitor or a substrate, confirmation of essentiality, and the identification of potent growth inhibitors either in vitro or in an infection model. If novel target validation and subsequent inhibition are matched by an improved understanding of disease biology, then new antibiotics could have the potential to shorten the duration of therapy, prevent resistance development and eliminate latent disease.     

Mitochondrial and plastid functions as antimalarial drug targets

Malaria parasites possess three genomes: the nuclear chromosomes, the mitochondrial genome, and the plastid genome. Realization that the parasites contain a plastid remnant with its own genome has created much excitement not only from a basic biological point of view but also from the prospects for developing new antimalarial drugs. Both the mitochondrial and the plastid genomes are the smallest examples of their kind known to date. The plastid appears to be derived from an ancestral secondary endosymbiotic event. Interestingly, the main functions usually associated with a mitochondrion and a plastid, i.e. oxidative phosphorylation and photosynthesis, do not appear to be conserved in malaria parasites. Completion of the parasite genome sequence has provided the opportunity to assess functions assigned to these highly derivatized organelles. It is clear that these organelles serve vital functions since interference with their activity is incompatible with parasite growth. A number of antimalarial compounds target functions of either the mitochondrion or the plastid. This review will survey our current understanding of mitochondrial and plastid functions with a view to identify processes that are or have a potential to be targets for antimalarial drugs.     

Endocannabinoids: new targets for drug development

The possible therapeutic use of marijuana s active principles, the cannabinoids, is currently being debated. It is now known that these substances exert several of their pharmacological actions by activating specific cell membrane receptors, the CB1 and CB2 cannabinoid receptor subtypes. This knowledge led to the design of synthetic cannabinoid agonists and antagonists with high therapeutic potential. The recent discovery of the endocannabinoids, i.e. endogenous metabolites capable of activating the cannabinoid receptors, and the understanding of the molecular mechanisms leading to their biosynthesis and inactivation, opened a new era in research on the pharmaceutical applications of cannabinoids. Ongoing studies on the pathological and physiological conditions regulating the tissue levels of endocannabinoids, and on the pharmacological activity of these compounds and their derivatives, may provide a lead for the development of new drugs for the treatment of nervous and immune disorders, cardiovascular diseases, pain, inflammation and cancer. These studies are reviewed in this article with special emphasis on the chemical features that determine the interaction of endocannabinoids with the proteins mediating their activity and degradation.     

Arteether, a new antimalarial drug: synthesis and antimalarial properties

Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.