Site-Specifically Modified Peptide Inhibitors of Protein Tyrosine Phosphatase 1B and T‑Cell Protein Tyrosine Phosphatase with Enhanced Stability and Improved In Vivo Long-Acting Activity

Protein tyrosine phosphatase 1B (PTP1B) and TC-PTP can
function
in a coordinated manner to regulate diverse biological processes including
insulin and leptin signaling, T-cell activation, and tumor antigen
presentation, which makes them potential targets for several therapeutic
applications. We have previously demonstrated that the lipidated BimBH3
peptide analogues were a new class of promising PTP1B inhibitors with
once-weekly antidiabetic potency. Herein, we chemically synthesized
two series of BimBH3 analogues via site-specific modification and
studied their structure–activity relationship. The screened
analogues S2, S6, A2–14, A2–17, A2–20, and A2–21 exhibited an improved PTP1B/TC-PTP dual inhibitory
activity and achieved good stability in the plasma of mice and dogs,
which indicated long-acting potential. In mouse models of type 2 diabetes
mellitus (T2DM), the selected analogues S6, S7, A2–20, and A2–21 with an
excellent target activity and plasma stability generated once-weekly
therapeutic potency for T2DM at lower dosage (0.5 μmol/kg).
In addition, evidence was provided to confirm the cell permeability
and targeted enrichment of the BimBH3 analogues. In summary, we report
here that site-specific modification and long fatty acid conjugation
afforded cell-permeable peptidomimetic analogues of BimBH3 with enhanced
stability, in vivo activity, and long-acting pharmacokinetic profile.
Our findings could guide the further optimization of BimBH3 analogues
and provide a proof-of-concept for PTP1B/TC-PTP targeting as a new
therapeutic approach for T2DM, which may facilitate the discovery
and development of alternative once-weekly anti-T2DM drug candidates.