Proteins as Targets in Anti-Schistosomal Drug Discovery and Vaccine Development

Abstract

Proteins hardly function in isolation; they form complexes with other proteins or molecules to mediate cell signaling and control cellular processes in various organisms. Protein interactions control mechanisms that lead to normal and/or disease states. The use of competitive small molecule inhibitors to disrupt disease-relevant protein-protein interactions (PPIs) holds great promise for the development of new drugs. Schistosome invasion of the human host involves a variety of cross-species protein interactions. The pathogen expresses specific proteins that not only facilitate the breach of physical and biochemical barriers present in skin, but also evade the immune system and digestion of human hemoglobin, allowing for survival in the host for years. However, only a small number of specific protein interactions between the host and parasite have been functionally characterized; thus, in-depth understanding of the molecular mechanisms of these interactions is a key component in the development of new treatment methods. Efforts are now focused on developing a schistosomiasis vaccine, as a proposed better strategy used either alone or in combination with Praziquantel to control and eliminate this disease. This review will highlight protein interactions in schistosomes that can be targeted by specific PPI inhibitors for the design of an alternative treatment to Praziquantel.

Keywords: Sm-P80/Gla-Se; Sm-Tsp-2/Alhydrogel; Sm14/Gla-Se; praziquantel; protein–protein interactions; schistosomiasis.

Figure 1

Model proposing the survival mechanisms of schistosomes within the host by protease inhibitors. The cercariae penetrate the human skin using cercarial elastase, which secretes a protease inhibitor, SmSrpQ. This regulates the production of cercarial elastase, in this way protecting the cercariae from its own elastase (1). The presence of CE inhibitors, Elafin and Z-AAPF-CMK, inactivates CE, blocking SmSrpQ regulation, and thus, preventing successful host penetration (2). However, in their absence, the cercariae migrate through various tissues in the host. This stimulates an immune response in the human host, leading to the release of effector cells and specific proteases such as NE to defend the human body (2). To counteract the host’s immune response, schistosomules secrete various protease inhibitors (SmPi56, SmkI-1 and SjKI-1) and heat shock proteins to inhibit the effects of NE (3). In the small intestine (4), schistosomes escape digestion by digestive enzymes through the secretion of SjB6, which inhibits digestive proteases within the host (trypsin, chymotrypsin and pancreatic elastase). In the mesenteric veins of the host, adult worms prevent blood coagulation by secreting SmKI-1, which inhibits various blood-clotting factors, in this way interfering with blood flow to vital organs of the body (5). The worms survive and produce eggs to continue the infection cycle. These eggs are protected from the effects of pancreatic elastase by SjB10 and SmKI-1 (6).

Figure 2

Schematic diagram of the folding mechanism of the schistosomal Hsp60-Hsp10 complex. In the human host, schistosomes are exposed to extreme temperatures that result in unfolding of their proteins (1). Increased temperature conditions within the worm stimulate the expression of Hsp60, which binds the unfolded polypeptide (2). Hsp10 and ATP immediately bind to Hsp60, forming an Hsp60-Hsp10 complex that facilitates folding in an ATP-dependent manner (3). Protein folding is, therefore, expected to occur within 15–30 s prior to ATP hydrolysis (4), which leads to the release of the bound polypeptide (5), and thus, the worm regains functionality and survives. To block the chaperoning activity of Hsp60 in schistosomes, a type I Hsp60 inhibitor such as Mizoribine binds to Hsp60, blocking ATP and Hsp10 binding, and thus, preventing protein folding (6). A type II Hsp60 inhibitor, Epolactaene, binds the Cys442 residue, thus inactivating Hsp60 prior to binding of the unfolded polypeptide (7).