Plasmodium falciparum M1-Aminopeptidase: A Promising Target for the Development of Antimalarials

Abstract

Malaria is a devastating human parasitic disease that receives enhanced attention due to the emergence of resistance to traditional drugs. Thus, the search for new molecular targets is a major goal. PfAM1 is an aminopeptidase from Plasmodium falciparum, William H. Welch 1897, belonging to the M1 family of metalloproteases, which is a promising target of inhibitors to block the intra-erythrocytic stages of the parasite. Since its identification in 1998, many efforts have been done to validate PfAM1 as an appropriate target of antimalarials. The present work is a critical review of the main structural, functional and kinetic characteristics of PfAM1, as well as a summary of the effects of key inhibitors at molecular and cellular levels. The systematization of experimental results should contribute to a better understanding of the properties of PfAM1 as a target of antimalarials and promote research projects focused on the development of PfAM1 inhibitors.

P1′ Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases

“…They are also connected with several infections caused by bacteria, for example, meningitis caused by Neisseria meningitides [74], or protozoans, for example, malaria transmitted by Plasmodium falciparum. The parasite aminopeptidase of this species is involved in the digestion of short hemoglobin-derived peptides and has been rated as a highly prospective therapeutic target [75,76].…”

Aminobenzosuberone Scaffold as a Modular Chemical Tool for the Inhibition of Therapeutically Relevant M1 Aminopeptidases

“…This common substrate specificity, together with a very conserved structure and catalytic mechanism, makes the development of highly selective inhibitors of a given metallo-aminopeptidase obviously challenging [ 11 , 28 , 29 , 30 , 31 ]. Thereby the most notable inhibitors, depicted in Figure 1 , consist in tetrahedral intermediate mimics, as for the widely used bestatin [ 32 ] and phosphinic [ 33 ]/phosphonic [ 34 ] acid derivatives, or zinc-chelating group inserted in a peptide-like scaffold, as for hydroxamic acids [ 35 , 36 , 37 ].…”

Selective inhibition of PfA-M1, over PfA-M17, by an amino-benzosuberone derivative blocks malaria parasites development in vitro and in vivo

“…PfA-M1, initially discovered through the isolation of its gene, was then affiliated to the highly conserved M1 family of metalloprotease with an active site closer to that of Escherichia coli PepN than to that of the mammalian members (including APN, APA, IRAP, ERAP2) [ 24 ]. The first biochemical and enzymatic studies were done using the purified native enzyme, revealing its optimal activity at pH 7.4, its dependence on zinc, and its complex maturation in iRBC, from a full length ~ 126 kDa form named p126 to three forms of ~ 120, ~ 96 and ~ 68 kDa named p120, p96 and p68 [ 21 , 24 , 35 , 36 ]. The p35 C-terminal domain remains associated to the p68 form to yield the p68/p35 form of the enzyme [ 35 ], the in vivo meaning and/or relevance of this cleavage needing to be understood.…”

“…A recombinant form of the enzyme corresponding to monomeric p96 was produced in Escherichia coli allowing the determination of its 3D structure in 2009, including, later a variant of PfA-M1 in which the S1 pocket was altered [ 31 , 37 ]. Direct screening experiments on the native enzyme [ 38 , 39 ] then on various recombinant forms as well as docking investigations [ 40 , 41 ] have provided a series of inhibitors that display submicromolar to dozen nanomolar Ki/IC50 values and submicromolar IC 50 values on parasites growth [ 10 , 20 , 31 , 36 , 38 , 39 , 42 – 45 ]. Some inhibitors have also been shown to decrease or suppress parasitaemia in murine models of malaria [ 46 , 47 ].…”