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ARS Home » Southeast Area » Oxford, Mississippi » Natural Products Utilization Research » Research » Publications at this Location » Publication #330807
Research Project: Discovery and Development of Natural Products for Pharmaceutical and Agrochemical Applications II

Location: Natural Products Utilization Research

Title: Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads

Author
item JAIN, JAGRATI - University Of Mississippi
item JAIN, SURENDRA - University Of Mississippi
item WALKER, LARRY - University Of Mississippi
item TEKWANI, BABU - University Of Mississippi

Submitted to: Biomed Central Pharmacology and Toxicology Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/23/2017
Publication Date: 6/2/2017
Citation: Jain, J., Jain, S., Walker, L., Tekwani, B. 2017. Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads. Biomed Central Pharmacology and Toxicology Journal. doi:10.1186/s40360-017-0147-4.

Interpretive Summary: Worldwide, malaria caused 438,000 deaths and there had been estimated 214 million new cases of malaria in 2015 alone, according to the most recent estimates of the world health organization. In African countries, Plasmodium falciparum is dominant and responsible for 90% of deaths. Drug resistance of P. falciparum is the greatest bottleneck in the fight against malaria, as the parasite has developed resistance to most of the drugs presently used for the treatment of malaria. These factors have led to the earnest need to discover new molecular targets and identify new leads against those targets. The ubiquitin/proteasome pathway is the principal system for degradation of proteins in eukaryotes. Ubiquitin is a highly conserved polypeptide that covalently attaches to target proteins through the combined action of ubiquitin-activating enzyme (E1), conjugating enzyme (E2) and a protein ligase (E3). The endoplasmic reticulum associated degradation (ERAD) system of Plasmodium falciparum, composed of ubiquitin-activating enzyme (UBA1), ubiquitin-conjugating enzyme (UBC) and E3 ubiquitin ligase (HRD1), is essential for the parasite’s survival. The P. falciparum E3 ligase is significantly variable and divergent compared to the homologs from other eukaryotes, which make the E3 ligase a parasite-specific target. A set of selected E3 ubiquitin ligase inhibitors were tested in vitro against P. falciparum. Among these, JNJ 26854165, HLI 373 and Nutlin 3 showed significant activity against both chloroquine-sensitive (D6) and -resistant (W2) strains of P. falciparum and were significantly less cytotoxic to mammalian cells. The E3 ligase inhibitors blocked the development of P. falciparum parasite at the trophozoite stage, resulting in accumulation of distorted trophozoites and immature schizonts. The ubiquitin/proteasome functions may be important for schizont maturation. Further investigations on the lead E3 ligase inhibitors promise new understanding of the importance of E3 Ligase functions in the malaria parasite, and may provide a viable antimalarial-target and new classes of antimalarial drug leads.

Technical Abstract: The ubiquitin/proteasome pathway is the principal system for degradation of proteins in eukaryotes. Ubiquitin is a highly conserved polypeptide that covalently attaches to target proteins through the combined action ofubiquitin-activating enzyme (E1), conjugating enzyme (E2) and a protein ligase (E3). Endoplasmic reticulum associated degradation (ERAD) system of Plasmodium falciparum, composed of ubiquitin-activating enzyme (UBA1), ubiquitin-conjugating enzyme (UBC) and E3 ubiquitin ligase (HRD I), is essential for the parasite's survival. The P. falciparum E3 ligase is significantly variable and divergent compared to the homologs from other eukaryotes, which make the E3 ligase a parasite-specific target. A set of selected E3 ubiquitin ligase inhibitors were tested in vitro against Plasmodiumfalciparum. Among these, JNJ 26854165, HLI 373 and Nutlin 3 showed significant activity against both chloroquine-sensitive (D6) and -resistant (W2) strains of P. falciparum and were significantly less cytotoxic to the mammalian cells. The E3 ligase inhibitors blocked the development of P.falciparum parasite at trophozoite stage resulting in accumulation of distorted trophozoites and immature schizonts. The ubiquitin/proteasome functions may be important for schizont maturation. Further investigations on the lead E3 ligase inhibitors promise new understanding of the importance of E3 Ligase functions in the malaria parasite, and may provide antimalarial-target and new classes of antimalarial drug leads.