Current status of artemisinin and its derivatives as antimalarial drugs

Dhingra, Vikas; Rao, K. Vishweshwar; Narasu, M. Lakshmi

doi:10.1016/s0024-3205(99)00356-2

Cited by 220 publications

(131 citation statements)

References 131 publications

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“…[14][15][16] Isoprenoids have been recognized as anticancer and antimalarial drugs 17,18 as well as potential gasoline replacements. 19,20 Chemical synthesis or modification of isoprenoids is difficult due to their structural complexity, and therefore the large scale of production of isoprenoids in industry is hindered.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation Mechanism of Phosphomevalonate Kinase: Implications for Rational Engineering of Isoprenoid Biosynthetic Pathway Enzymes

Huang

Wei

et al. 2016

J. Phys. Chem. B

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Mevalonate pathway is of important clinical, pharmaceutical and biotechnological relevance.However, lack of the understanding of the phosphorylation mechanism of the kinases in this pathway has limited rationally engineering the kinases in industry. Here the phosphorylation reaction mechanism of a representative kinase in the mevalonate pathway, phosphomevalonate kinase, was studied by using molecular dynamics and hybrid QM/MM methods. We find that a conserved residue (Ser106) is reorientated to anchor ATP via a stable H-bond interaction. In addition, Ser213 located on the α-helix at the catalytic site is repositioned to further approach the substrate, facilitating the proton transfer during the phosphorylation. Furthermore, we elucidate that Lys101 functions to neutralize the negative charge developed at the β-, γ-bridging oxygen atom of ATP during phosphoryl transfer. We demonstrate that the dissociative catalytic reaction occurs via a direct phosphorylation pathway. This is the first study on the phosphorylation mechanism of a mevalonate pathway kinase. The elucidation of the catalytic mechanism not only sheds light on the common catalytic mechanism of GHMP kinase superfamily, but also provides the structural basis for engineering the mevalonate pathway kinases to further exploit their applications in the production of a wide range of fine chemicals such as biofuels or pharmaceuticals.3

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Section: Introductionmentioning

confidence: 99%

Phosphorylation Mechanism of Phosphomevalonate Kinase: Implications for Rational Engineering of Isoprenoid Biosynthetic Pathway Enzymes

Huang

Wei

et al. 2016

J. Phys. Chem. B

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“…According to the number of isoprene units in their backbone, the terpenoids are classified into hemiterpinoids (one isoprene unit, 5C), monoterpinoids (two isoprene units, 10C), sesquiterpinoids (three isoprene units, 15C), diterpinoids (four isoprene units, 20C), sesterterpinoid (five isoprene unit, 25C) and so on [36]. Many terpenoids show therapeutic potential as antibacterial [37], anti-viral [38], anti-malarial [39], anti-parasitic [40], anti-hyperglycemic [41], anti-inflammatory [42] and anti-cancer agents [36]. One such terpenoid compound that holds tremendous potential for the prevention/treatment of cancer is zerumbone (2,6,9,9-tetramethyl-[2E,6E,10E]-cycloundeca-2,6,10-trien-1-one), a cyclic eleven-membered sesquiterpene, isolated from the rhizomes of the tropical plant Zingiber zerumbet Smith.…”

Section: Introductionmentioning

confidence: 99%

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

Prasannan

Kalesh

Shanmugam

et al. 2012

Biochemical Pharmacology

126

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“…With regard to artemisinin and malaria, it is believed that 2 sequential steps ate involved. Activation of artemisinin inside the malarial parasite by heme or other iron systems results in cleavage of endoperoxide bridges and generation of free radicals, and formation of covalent complexes between these free radicals and malaria-specific proteins or specific receptors (MESHNICK et al, 1991(MESHNICK et al, , 1993ZHANG et al, 1992;KAMCHONW~NGPAISAN & MESHNICK, 1996;MESHNICK, 1998;DHINGRA et al, 2000). Both the parent artemisinin compound and its more active derivative artemether (HIEN & WHITE, 1993) are rapidly metabolized to the biologically active dihvdroartemisinin WHITE.…”

Section: Discussionmentioning

confidence: 99%

“…Summarizing the data dealing with the interaction of artemislnin with haemin, heme and free iron, a two-step mechanism of action against malaria parasites has been proposed (KAMCHON@ONGPAISAN & MRSH-NICK, 1996;MESHNICK et al, 1996;MESHNICK, 1998;DHINGRA et al, 2000). Artemisinln is activated by intraparasitic iron, which catalyses the cleavage of the endoperoxide bridge and the generation of free radicals.…”

Section: Introductionmentioning

confidence: 99%

Artemether administered together with haemin damages schistosomes in vitro

Shuhua

Chollet

Utzinger

et al. 2001

Transactions of the Royal Society of Tropical Medicine and Hygi

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We conducted experiments in vitro to assess the effect of artemether in combination with haemin on adult Schisrosoma japonicum, S. mansoni and S. haematobium. When schistosomes were maintained in a medium containing artemether at concentrations of 20 p,g/mL or less for 72 h, no apparent effect on the schistosomes was seen, When the medium contained 50 or 100 pg/mL haemin as well as artemether, the schistosomes showed decreased motor activity 2-24 h after exposure, which was followed by the staining of the whole worm body a reddish-yellow colour, dilatation of the intestine, and extensive vesiculation of the tegument. Some of the schistosomes died 24 h after exposure? and almost all died within 48-72 h. When scbistosomes were exposed to the same concentrations of haemm alone, they were stained a light yelfow colout but there was no apparent effect on their survival. Our findings suggest that artemether interacts with haemin to exert a toxic effect on the worms, which might be of importance in the further elucidation of the mechanism of action of aaemether on schistosomes.

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Current status of artemisinin and its derivatives as antimalarial drugs

Cited by 220 publications

References 131 publications

Phosphorylation Mechanism of Phosphomevalonate Kinase: Implications for Rational Engineering of Isoprenoid Biosynthetic Pathway Enzymes

Phosphorylation Mechanism of Phosphomevalonate Kinase: Implications for Rational Engineering of Isoprenoid Biosynthetic Pathway Enzymes

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

Artemether administered together with haemin damages schistosomes in vitro

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