Abstract
Background: Epithelial ovarian cancer remains one of the leading variants of gynecological cancer with a high mortality rate. Feasibility and technical competence for screening and detection of epithelial ovarian cancer remain a major obstacle and the development of point of care diagnostics (POCD) may offer a simple solution for monitoring its progression. Cathepsins have been implicated as biomarkers for cancer progression and metastasis; being a protease, it has an inherent tendency to interact with Cystatin C, a cysteine protease inhibitor. This interaction was assessed for designing a POCD module. Methods: A combinatorial approach encompassing computational, biophysical and electron-transfer kinetics has been used to assess this protease-inhibitor interaction. Results: Calculations predicted two cathepsin candidates, Cathepsin K and Cathepsin L based on their binding energies and structural alignment and both predictions were confirmed experimentally. Differential pulse voltammetry was used to verify the potency of Cathepsin K and Cathepsin L interaction with Cystatin C and assess the selectivity and sensitivity of their electrochemical interactions. Electrochemical measurements indicated selectivity for both the ligands, but with increasing concentrations, there was a marked difference in the sensitivity of the detection. Conclusions: This work validated the utility of dry-lab integration in the wet-lab technique to generate leads for the design of electrochemical diagnostics for epithelial ovarian cancer.
Highlights
Epithelial ovarian cancer (EOC) is the fourth most common cause of cancer-associated death in women in the developing world [1]
At S3 site the interacting pocket residues identified by Computed Atlas of Structure Topography of proteins (CASTp) were Gln60 and Gly68
The major interacting residues which were identified in the S20 site of cysteine proteases (CPs) are Asn 18, Gln19, Gly20, Cys22, Gly23, Ser24 and Cys25
Summary
Epithelial ovarian cancer (EOC) is the fourth most common cause of cancer-associated death in women in the developing world [1]. CA125 and HE4 have been consistently utilized as clinically approved biomarkers for EOC detection but they have associated advantages and disadvantages [4,5]. Cathepsins are highly expressed in a multitude of human cancers and have been found to be associated with tumor metastasis [7]. This family encompasses cysteine proteases (CPs) (B, C, F, H, L, K, O, S, V, W, X, Z), serine proteases (A and G) and aspartic proteases (D and E) [8]. CPs are monomeric proteins with molecular weight ranging between 20 and 35 Kda with their overall structure
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