Abstract
Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar levels resulting primarily from either a lack of insulin production or insulin resistance. Insulin elicits its effects by activating the Insulin Receptor (IR) which is responsible for glucose uptake and promotes insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of IR signaling and is responsible for dephosphorylating the tyrosine phosphorylated IR. Inhibition of PTP1B could thus promote glucose uptake [1]. Early PTP1B inhibitors, such as charged active site-directed analogs, showed poor cell membrane permeability. Subsequent uncharged mimetics overcome this initial hurdle however specificity over T-cell protein tyrosine phosphatase (TCPTP) was another challenge that needed to be overcome. Herein is an overview of the challenges faced for targeting PTP1B. These include the evaluation of compounds that target the active site, allosteric site, and finally covalent inhibition of this potentially viable drug target.
Highlights
Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar levels resulting primarily from either a lack of insulin production or insulin resistance
Active site directed Protein tyrosine phosphatase 1B (PTP1B) inhibitors faced the limitation of poor cell membrane permeability
This issue was tackled by developing either un-charged or amphoteric inhibitors. These inhibitors mainly interacted with the active site of the enzyme and failed to provide selectivity over other PTPs, especially T-cell protein tyrosine phosphatase (TCPTP)
Summary
Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar levels resulting primarily from either a lack of insulin production or insulin resistance. Li et al identified a series of lipid like salicylic acid-based derivatives as potent and membrane-permeable PTP1B inhibitors (18-20, Figure 7). Liu et al developed a series of 2-substituted ethenesulfonic acid ester derivatives as potent PTP1B inhibitors possessing sufficient cell membrane permeability (Figure 8). Apart from the issue of low cell membrane permeability, pTyr mimetic PTP inhibitors face an issue of selectivity for PTP1B over other PTPs, especially T-cell protein tyrosine phosphatase (TCPTP).
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