Structural Insights Into Key Plasmodium Proteases as Therapeutic Drug Targets

Abstract

Malaria, caused by protozoan of genus Plasmodium, remains one of the highest mortality infectious diseases. Malaria parasites have a complex life cycle, easily adapt to their host’s immune system and have evolved with an arsenal of unique proteases which play crucial roles in proliferation and survival within the host cells. Owing to the existing knowledge of enzymatic mechanisms, 3D structures and active sites of proteases, they have been proven to be opportune for target based drug development. Here, we discuss in depth the crucial roles of essential proteases in Plasmodium life cycle and particularly focus on highlighting the atypical “structural signatures” of key parasite proteases which have been exploited for drug development. These features, on one hand aid parasites pathogenicity while on the other hand could be effective in designing targeted and very specific inhibitors for counteracting them. We conclude that Plasmodium proteases are suitable as multistage targets for designing novel drugs with new modes of action to combat malaria.

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

“…An important observation indicated that FPs and other proteases contributing in hemoglobin degradation and egress and de novo RBCs invasion cascade use similar mechanisms for biological control, but use different specific means mediating interactions with their substrates and inhibitors [39] . Also in another review, this extension motif was suggested as a novel anti-malarial drug target [40] .…”

“…Similar to other papain family plasmodial CPs, the C-terminal of SERAs have an extension motif (10 amino acids) to bind with its substrate [39] . Also, this extension motif was suggested as a novel anti-malarial drug target [40] .…”

Aminobenzosuberone derivatives as PfA-M1 inhibitors: Molecular recognition and antiplasmodial evaluation

“…They are involved in a number of vital pathways which are essential for parasite survival: red blood cell (RBC) invasion, hemoglobin (Hb) degradation, egress. [3] Among these pathways, Hb degradation provides amino acids necessary to the metabolism and survival of the parasites inside erythrocytes [4][5][6][7], and also reduces the colloidosmotic pressure within the host RBCs and thus preventing their premature lysis. [8,9] One of these attractive protease targets is the Plasmodium falciparum M1 aminopeptidase, PfA-M1.…”

“…[10,12,13,18] Given these results, PfA-M1 seems to be an essential protein and hence, a very attractive validated target for the development of novel antiplasmodial drugs. [3,19,36,37] In addition, blocking PfA-M1 catalytic activity with low molecular weight inhibitors is fatal for the parasite without major toxicities for the host. [16,38] Most of the PfA-M1 inhibitors (Table 1) consist of tetrahedral intermediate mimics, such as the well-known aminopeptidase inhibitor bestatin 1, or as phosphinic acid 2, or zinc-chelating group inserted in a peptide-like scaffold, such as hydroxamic acids 3-5.…”

Repurposing the McoTI-II Rigid Molecular Scaffold in to Inhibitor of ‘Papain Superfamily’ Cysteine Proteases

“…PLCPs in parasites are also known for their indispensable roles in parasite growth and cell differentiation, signalling and host invasion [ 11 , 13 , 14 , 15 , 16 ]. Their suitability as a potential drug target for antiparasitic chemotherapy is very well validated [ 15 , 17 , 18 ]. Therefore, the design and synthesis of cysteine protease inhibitors (CPIs) holds significant value in medicine and biotechnology.…”