Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

Abstract

Objectives:Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites.Methods:The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs.Results:Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite.Conclusion:Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug resistance.

The NTP generating activity of pyruvate kinase II is critical for apicoplast maintenance in Plasmodium falciparum

“…GTP is required for multiple steps of protein translation including translation initiation, peptide chain elongation, translation termination, and ribosome recycling, which are processes mediated by translational GTPases ( Maracci and Rodnina, 2016 ). ATP is required for tRNA charging by aminoacyl-tRNA synthetases ( Pang et al, 2014 ), iron-sulfur cluster formation by the SufC ATPase ( Saini et al, 2010 ), DNA gyrase subunits ( Mukherjee and Sadhukhan, 2016 ), as well as numerous other energy requiring pathways within the organelle ( Lim and McFadden, 2010 ). Additionally, NTPs and dNTPs are required for transcription and DNA replication, respectively ( Joyce and Steitz, 1995 ; Nudler, 2009 ).…”

“…With increasing resistance to current front-line antimalarials, there is a crucial need to find new therapeutic interventions with novel mechanisms of action ( Dondorp et al, 2009 ; Trape, 2001 ). The apicoplast organelle within the parasite has often been considered as a source of new drug targets since it is required for blood-stage survival, in addition to possessing evolutionarily distinct biochemical pathways that are not present in the human host ( Goodman and McFadden, 2013 ; Janouskovec et al, 2010 ; Mukherjee and Sadhukhan, 2016 ). One pathway within the apicoplast that represents a source of potential drug targets is carbon metabolism, due to its predicted role in supporting metabolism within the organelle.…”

Review of Atypical Organometallic Compounds as Antimalarial Drugs

“…In other works, the Plasmodium apicoplast has been predicted to be involved in the synthesis of heme, fatty acids, and isoprenoids [72] even though its most biological relevant mechanism is yet to be deciphered [73]. It is important to note that biological processes essential to the parasite are quite unique from that of its mammalian As the apicoplast's potential as an antimalarial drug target has been highly recommended [74]. So far, antimalarial drugs such as ciprofloxacin, rifampicin, and doxycycline have targeted the organelle's DNA replication, transcription, and translation [75].…”

2-Phenoxy-3-Trichloromethylquinoxalines Are Antiplasmodial Derivatives with Activity against the Apicoplast of Plasmodium falciparum

“…This organelle contains the second smallest known circular genome for a plastid (35 kilobases) which encodes for proteins that are targeted to the apicoplast [15]. Although not photosynthetic, the apicoplast performs several essential anabolic functions for the parasite, including isoprenoid precursors biosynthesis, fatty acids biosynthesis, heme biosynthesis, and iron-sulfur cluster assembly [16].…”