Venom-based peptide therapy: insights into anti-cancer mechanism

Abstract

The 5-year relative survival rate of all types of cancer has increased significantly over the past three decades partly due to the targeted therapy. However, still there are many targeted therapy drugs could play a role only in a portion of cancer patients with specific molecular alternation. It is necessary to continue to develop new biological agents which could be used alone and/or in combination with current FDA approved drugs to treat complex cancer diseases. Venom-based drugs have been used for hundreds of years in human history. Nevertheless, the venom-origin of the anti-cancer drug do rarely appear in the pharmaceutical market; and this is due to the fact that the mechanism of action for a large number of the venom drug such as venom-based peptide is not clearly understood. In this review, we focus on discussing some identified venom-based peptides and their anti-cancer mechanisms including the blockade of cancer cell proliferation, invasion, angiogenesis, and metastasis (hallmarks of cancer) to fulfill the gap which is hindering their use in cancer therapy. Furthermore, it also highlights the importance of immunotherapy based on venom peptide. Overall, this review provides readers for further understanding the mechanism of venom peptide and elaborates on the need to explore peptide-based therapeutic strategies.

Keywords: anticancer mechanism; metastasis; signaling pathway; targeted therapy; venom.

Figure 1. Current venom-based drugs in the market used for different forms of human disease

Figure 2. 3D structure of venom peptides

(A and B) Amphipathic peptides melittin (PDB ID:2MLT) and mastoparan (PDB ID: 2CZP) exhibiting the increase of hydrophobicity in the alpha helix (yellow region), respectively. (C and D) Another key feature of venom peptides, disulfide bridges show in ion channel blocker chlorotoxin (PDB ID: 1CHL) and mitochondrial membrane binding peptide cardiotoxin III (PDB ID: 2CRT), respectively. (E) Jararhagin, a metalloprotease with multiple alpha helices and beta sheets and its 3D structure is modeled from SWISS-MODEL. Figures were constructed by Discovery Studio version 2016.

Figure 3. Schematic representation of PLA2 action on glycerophospholipids

PLA2 enzymes catalyze the hydrolysis of the sn-2 ester bond in glycerophospholipids to produce free fatty acids and lysophospholipids.

Figure 4. Chlorotoxin, Soricidin, and their related peptides

(A) The sequence alignment of Chlorotoxin, BmKCTa, GaTx1, GaTx2, and AaCtx. (B) The phylogenetic tree of Chlorotoxin, BmKCTa, GaTx1, GaTx2, and AaCtx. From an evolutionary point of view, chlorine toxins, BmKCTa and GaTx1 may be relatively closer relationship than AaCtx and GaTx2. (C) The sequence alignment of Soricidin, SOR-C27, and SOR-C13.

Figure 5. Molecular modeling between Integrin α_vβ₃ (PDB: 1JV2) and disintegrin salmosin (PDB: 1L3X) based on the crystal structure of α_vβ₃ complex (PDB: 1L5G)

(A) Ribbon modeling is depicting the interaction between salmosin and integrin α_vβ₃ receptor. Salmosin binds to the hinge created between α_v and β₃ subunits of integrin. Yellow-subunit α_v, green-subunit β₃ and red-salmosin (the ball structure represents the RGD site). (B) The integrin α_vβ₃ receptor surface of the RGB motif interactions are shown in the charge mode (PDB 1L5G). Figures were constructed by Discovery Studio version 2016.