Artemisinins - an important class of antimalarial drug - Essay Example

In order to check the statistical significance of the observations, Mutations were introduced in various mammalian and Plasmodium isolates. ATPase assay was performed to determine Ki values of each drug on the mutant as compared to its wild-type SERCA. The introduction of Leucine at position 263 in place of Alanine in the Plasmodium vivax search resulted in a 3 fold increase (Ki=63nM+/-12) as compared to wild-type PfATP6 (Ki=169+/-31) in the sensitivity of Artemisinin. Whereas the introduction of leucine at position 263 in the place of serine in P.

berghei decreases the sensitivity by 3-fold (Ki= 530nm+/-84). IC50 values showed P.vivax (IC50-1.3nM)is more susceptible to artesunate than P.falciparum(IC50-4.2nM).Artemisone a semisynthetic derivative of artemisinin is more potent against PvSERCA (<100 pM). Mammalian and X.laevis SERCA are resistant to artemisinin due to a presence of glutamic acid.Mutating Glutamic acid to leucine at position 255 in SERCA 1 introduces artemisinin sensitivity to mammalian SERCA. Mutation of glutamic acid at position 263 to leucine in PfATP6 (equivalent to Glu 255 in mammalian serca) preserves thaspargin sensitivity but abolishes artemisinin sensitivity.

A detailed structural analysis of the mammalian SERCA and PfATP6 confirms our hypothesis. Thapsigargin binds in a cleft between helices M3 and M7 with L6/7 loop forming the apex of this pocket. Electrostatic interaction between residues in this loop and helix M7 results in the change of protein structure and the binding site gets blocked.. IC50 values showed P.vivax (IC50-1.3nM)is more susceptible to artesunate than P.falciparum(IC50-4.2nM).Artemisone a semisynthetic derivative of artemisinin is more potent against PvSERCA (