Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum

Abstract

Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkylesters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC 50 values (8.5 ± 0.8 mM, 9.5 ± 0.2 mM and 4.9 ± 1.3 mM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.

Dissecting a novel allosteric mechanism of cruzain: A computer-aided approach

“…Several findings support the existence of allosteric modulation in the papain-like proteases [29–35]. One key example is the work of Novinec et al ., where several allosteric sites of human cathepsin K (HCatK) and the sector residues potentially mediating allosteric communication in the aforementioned protein family were identified employing the statistical coupling analysis (SCA) method (Fig 1) [36].…”

Chalcone hybrids and their antimalarial activity

“…Besides the chalcone hybrids mentioned above, chalcone–furan/thiophene, [ 95,96 ] chalcone–indole, [ 97 ] chalcone–pyrimidine, [ 98 ] and chalcone–sulfamide [ 99–101 ] hybrids also showed certain antiplasmodial activity, but the majority of them were not superior to the references.…”

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (2): Plasmodium spp.

“…Combined structural biology tools and mass spectrometry enabled investigators to characterize the allosteric mechanism for inhibition of new non-peptidic organic compounds against FP-2 activity. The investigators demonstrated that compound 66 is the best non-competitive inhibitor that showed allosteric binding between FP-2 catalytic site and the hemoglobin binding arm [139] . As previously reported, certain residues at the interface of FPs pro-and mature domain are essentially required for prodomain dissociation and FPs auto-processing (hot spot) [38] .…”