Abstract
Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite Plasmodium falciparum, aspartyl proteases of P. falciparum (plasmepsins) and the Sars-CoV-2 viral proteases. Despite some unfulfilled expectations over previous decades, the three reviewed targets clearly demonstrate that selective protease inhibitors provide effective therapeutic solutions for the two most impacting infectious diseases nowadays—malaria and COVID-19.
Highlights
Infectious diseases, along with starvation, limited water resources and the lack of shelter, are among the main factors threatening the health and prosperity of the world’s growing human population
IX/X inhibitors can be used for selective targeting of the malarial parasite, but novel compounds should be assayed for inhibitory activity against the main human proteases, cathepsins D and E, and risks should be further assessed in animal studies
This review focuses on the three most significant examples of successful progress in determining enzymatic targets for novel protease-based drug therapies
Summary
Infectious diseases, along with starvation, limited water resources and the lack of shelter, are among the main factors threatening the health and prosperity of the world’s growing human population. Significant proportions of infectious diseases are caused by parasites [1], the most common human infections being toxoplasmosis, ascariasis, ancylostomiasis and trichomoniasis. Uncatalyzed proteolysis is extremely slow, which is why living organisms have developed enzymes catalyzing peptide bond hydrolysis. Proteases play key roles in almost every biological phenomenon inside and outside individual organisms To their typical roles belongs the activation of other enzymes by their targeted processing, leading to the creation of active sites accessible to substrates or, the inactivation of proteins by their proteolytic degradation [4]. The majority of them are represented by metallo-, serine, aspartyl, cysteine and threonine proteases Metalloproteases are those that have a divalent metal ion bound to residues at a catalytic site, while others are classified with respect to catalytic amino acid residues in the active site. Serine proteolytic enzymes are the most abundant in nature, followed by metallo-, cysteine, aspartate and threonine proteases, respectively [6]
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