Selected gold compounds cause pronounced inhibition of Falcipain 2 and effectively block P. falciparum growth in vitro

A number of structurally diverse gold compounds were evaluated as possible inhibitors of Falcipain 2 (Fp2), a cysteine protease from P. falciparum that is a validated target for the development of novel antimalarial drugs. Remarkably, most tested compounds caused pronounced but reversible inhibition of Fp2 with Ki values falling in the micromolar range. Enzyme inhibition is basically ascribed to gold binding to catalytic active site cysteine. The same gold compounds were then tested for their ability to inhibit P. falciparum growth in vitro; important parasite growth inhibition was indeed observed. However, careful analysis of the two sets of data failed to establish any direct correlation between enzyme inhibition and reduction of P. falciparum growth suggesting that Fp2 inhibition represents just one of the various mechanisms through which gold compounds effectively antagonize P. falciparum replication.

Gold compounds, may act as effective inhibitors of the essential P. falciparum enzyme, Falcipain 2.Figure optionsDownload as PowerPoint slideHighlights
► A number of structurally diverse gold compounds produce relevant but reversible inhibition of Falcipain 2 activity.
► Enzyme inhibition most likely arises from gold binding to catalytic active site cysteine.
► These gold compounds inhibit of P. falciparum growth in vitro.
► No direct correlation between Falcipain 2 inhibition and reduction of P. falciparum growth.