Rational Design Of Novel Inhibitors Of Brugia Malayi Trehalose 6-Phosphate Phosphatase (Bm -16pp) As Potent Anti-Filarial Agent

Abstract

Trehalose is a sugar commonly found in archaeon, bacteria, fungi, plants, and invertebrates. It is utilized as an energy source and upregulated during stress conditions such as thermal fluctuations and oxidative stress. As mammals do not synthesize trehalose, trehalose biosynthetic pathways have become therapeutic targets for infectious diseases. The enzyme trehalose-6-phosphate phosphatase (T6PP) catalyzes the dephosphorylation of trehalose 6-phosphate to form trehalose. In its absence, the viability and virulence of bacteria, fungi, plants and nematodes are decreased. Hence T6PP is the focus of this study as a target for therapeutics of the disease’s tuberculosis and lymphatic filariasis.  The T6PP structure consists of a three-helix bundle N-terminal Domain connected via a short linker to the Rossmann-fold catalytic core domain and the α, β-fold cap domain, which together comprise the HAD superfamily (HADSF) phosphatase. Based on structural study and the inhibition kinetic analysis of wild-type and mutant B. malayi T6PP, there are two main binding sites such as the phosphoryl group binding site and the trehalose leaving group binding site that can be simultaneously targeted for inhibitor design. Accordingly, the glucose unit was modified for targeting the cap domain for induced cap closure over the active site via replacing an outer glycosyl unit by others biologically active scaffolds such as triazole moiety and the phosphate group of the trehalose-6-phosphate moiety was replaced by phosphate mimetic such a tosyl, sulphate etc, for targeting the active site of the catalytic domain.