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  • A spectrum of therapies came in order to counter

    2020-02-03

    A spectrum of therapies came in order to counter this misfortune, some of them are discussed below. However, the common problem faced by most of these drugs is their emerging resistance after a span of time. Some of the important drugs reported so far are as: Quinine-based antimalarial drugs (Fig. 1a) have served mankind for almost two centuries as the first and unique antimalarial drug [7]. Aryl amino alcohol antimalarial drugs in which Atovaquone (Fig. 1b) is the best example is a hydroxynaphthoquinone known for its inhibition of parasitic electron transport chain through the cytochrome C reductase complex and keeping the host mitochondrial functioning unaltered. [8], [9] Besides its high efficacy, this drug also showed a high range of recrudescence and later resistance [10]. More importantly Artemisinin (ARTs) based antimalarial drugs in which the key candidate, Artemisinin (ART) (Fig. 1c), a wonder drug for malaria was first extracted from wormwood Artemisia annua in China in the late 1960s, later its derivatives loomed as the frontline drugs for the treatment of malaria [11]. Artemisinin is a peroxide bridge containing sesquiterpene lactone endoperoxide [12]. It is an important drug for the resolution of malarial symptoms, but its mechanism of action is still unclear. Artemisinin combination therapies (ACT) overcame the failure due to resistance of the single antimalarial drugs and effectively worked to treat malaria over the past decade. However, resistance to the artemisinin components associated with Kelch13 has also been reported from some areas of Southeast Asia [13], [14]. Recently, the discovery DDD107498 (Fig. 1d) came into existence with a multiple stage antimalarial effect. It inhibits the parasitic protein synthesis and overcomes the emerging drug resistance [15]. To tackle the problem of drug resistance, various scientific affords are in pipeline to identify new compounds that can be used to treat malaria, with several compounds in clinical phases [16], [17]. The challenge for the future is to trace an alternative route to tackle the parasite. Although enormous efforts have been made to develop vaccines against malaria parasite but recently a milestone success in the field of malaria pathology came forth in the form of RTSs vaccine. This vaccine passed the clinical trial phase III [18]. Since the malaria parasite amasses the complicated life neuraminidase inhibitor including a series of obligate intracellular stages. Researchers have tried to find the most dependent stage of their lifecycle as drug targets against malaria. The drugs that target the enzymes which are involved directly or indirectly in the mitochondrial electron transport chain cytochrome bc1 complex have been validated with clinical trials [19]. Some important enzymes are: Dihydrofolate Reductase (DHFR), N-Myristoyltransferase (NMT), Phosphoethanolamine Methyltransferase PfPMT, and Dihydroorotate dehydrogenase (DHODH). Enzymes like dihydrofolate reductase (DHFR) or dihydropteroate synthase are very imperative for the formation of thymidine [20]. It has been reported that bc1 complex is important for producing oxidized ubiqinone to DHODH for pyrimidines synthesis [21]. For the survival of the parasite DHODH has a key importance because its involvement in the final stage of the pyrimidine biosynthesis and the parasite has no alternative to this pathway. So the inhibition of this enzyme may provide a complete cure to malaria.
    Dihydroorotate dehydrogenase (DHODH) Pyrimidines are obtain by the cells either through de novo in which ammonia acts as a starting material (derived from L-glu), bicarbonate, and L-asp, or by salvaging preformed pyrimidine bases (uracil, cytosine and thymine) or nucleosides (uridine, thymidine and cytidine). Human cells are able to utilize both the pathways but plasmodium species are exceptionally devoid of the pyrimidine salvage enzymes hence the de novo pathway serves as the only alternative for its survival. This was biochemically proved for the first time by analysis of the incorporation of radiolabeled precursors into nucleic acids [22]. The completion of the genome sequence has also supported the fact [23]. Among the pathogenic apicoplasts, plasmodium is the only genus that wholly depends on the de novo pyrimidine biosynthesis. Dehydrogenase enzymes which take part in malarial erythrocytic electron transport chain are NADH: ubiquinone oxidoreductase (PfNDH2), succinate: ubiquinone oxidoreductase (Complex II or SDH), glycerol-3-phosphate dehydrogenase, the malate quinone oxidoreductase (MQO) and DHODH. Among these, DHODH is present in both host as well as parasite. It has a pivotal role in the de novo pyrimidine biosynthesis of the parasite, as it acts as the main source of energy for it. DHODH is an important member of super family in the β/α–barrel structural class [24]. DHODH is a flavin mononucleotide (FMN) containing enzyme, catalyzes the oxidation of dihydroorotate to orotate and the reduction of FMN to dihydroflavin mononucleotide (FMNH2). Since the oxidation of l-dihydroorotic acid to orotic acid undergoes along the simultaneous reduction of FMN hence resulting the reduced FMNH2. The enzyme is then able to oxidize FMNH2 using different oxidants. The electron pair obtained from the oxidation of dihydroorotate to orotate is fed into the ETC, though flavin mononucleotide co-factor to ubiquinone, which itself is generated at the cytochrome bc1 complex, hence forms a bridge between metabolism and ETC [25] (see Fig. 2).