γ-lactone derivatives: a new promising class of protein tyrosine phosphatase B (MptpB) inhibitors as anti-TB agents

Despite the global effort to discover innovative antitubercular (TB) agents, this disease is still among the leading causes of mortality from a single infectious agent, surpassed in 2020 only by COVID-19. Mycobacterium tuberculosis (Mtb) can secrete two Low-Molecular-Weight Phosphatases (LMW-PTPs), MptpA and MptpB, inside the macrophage’s cytoplasm. These enzymes are essential for in vivo viability within the host cell because they interfere with the immune response. Therefore, PTPs were validated as promising targets for the development of innovative antitubercular agents. The aim of the current study was to synthesize innovative inhibitors of MptpB as potential anti-TB agents. To reach this goal a strategy that combined a receptor-based virtual screening (VS) protocol with biological tests was employed. The most interesting compound was subjected to SAR analysis for the development of several derivatives. Furthermore, the most promising inhibitors were encapsulated in self-assembly polymersomes to obtain an efficient delivery into the macrophages. Starting from a virtual screening campaign and subsequent structure elucidation studies guided by crystallographic analysis, the unexpected γ-lactone derivative VS1 (Figure 1) revealed a promising inhibitory activity on recombinant MptpB.3 SAR studies were employed for the design and synthesis of several VS1 derivatives that were tested against MptpB. Furthermore, PMPC-PDPA block-copolymers were used to encapsulate the most interesting compounds by a self-assembly technique. The polymersomes will be tested with human macrophages cell lines to assess their antimicrobial properties. The chemical structure of VS1 was fully characterized by NMR, IR, MS, and SC-XRD studies. The analysis of the X-ray data revealed an unexpected structure, different to that declared by the supplier, characterized by the γ-lactone scaffold. The structure of MptpB has an unusually large active site composed of 3 pockets: a primary phosphate binding pocket (P1) and two unique secondary pockets (P2 and P3) not present in human phosphatases. Preliminary docking studies hypothesized that the γ-lactone scaffold can rearrange the interaction with the active site to orientate the biggest moiety of the molecule always to the big P2 pocket and the smallest moiety to the P3 pocket.