Pharmacological inhibition of Bax-induced cell death: Bax-inhibiting peptides and small compounds inhibiting Bax

Abstract

Bax is an essential mediator of mitochondria-dependent programed cell death. Bax belongs to the Bcl-2 family of proteins and its activities are regulated through interaction with other member proteins in the Bcl-2 family. To date, several apoptosis-inducing drugs activating Bax have been developed, and some of them are already in the market as therapeutics against cancer. However, at present, there are no clinically effective pharmacological Bax inhibitors protecting essential cells. Previously, we developed Bax-Inhibiting Peptides (BIPs) that belong to the peptide group of Cell-Penetrating Peptides (CPPs). CPPs have the ability to deliver cargo molecules into the cell. In this review, we will describe the mechanism of action of BIPs together with the recent applications of BIPs in disease models in vitro and in vivo. However, BIPs have several limitations in their use to treat human diseases, and other types of Bax inhibitors need to be developed for future therapeutics. Recently, several groups reported the successful development of novel small compounds inhibiting Bax. We will review these Bax inhibitors to discuss current strategies to develop pharmacological Bax inhibitors. Impact statement Bax induces mitochondria-dependent programed cell death. While cytotoxic drugs activating Bax have been developed for cancer treatment, clinically effective therapeutics suppressing Bax-induced cell death rescuing essential cells have not been developed. This mini-review will summarize previously reported Bax inhibitors including peptides, small compounds, and antibodies. We will discuss potential applications and the future direction of these Bax inhibitors.

Long non-coding RNA growth arrest specific transcript 5 acting as a sponge of MicroRNA-188-5p to regulate SMAD family member 2 expression promotes myocardial ischemia-reperfusion injury

“…Bax among the most important pro-apoptotic genes in the plant, belongs to Bcl-2 family. Encoded Bax is available to repress Bcl-2 through forming a heterodimer with Blc-2 [ 23 , 24 ]. Additionally, caspase-3, as the most vital terminal splicing enzyme is a key gene [ 25 ] amid apoptosis.…”

Considerations on the Rational Design of Covalently Conjugated Cell-Penetrating Peptides (CPPs) for Intracellular Delivery of Proteins: A Guide to CPP Selection Using Glucarpidase as the Model Cargo Molecule

“…All five CPP5s are on our final candidates’ list, including “Bip 2”, “Bip 6” and “Bip 15” in the N-terminal conjugates, as well as “Bip 1”, in the C-terminal conjugates to CPG2. Among these CPP5s, “Bip 1”, “Bip 2”, and “Bip 6” have cytoprotective properties, while “Bip 15” is without any cytoprotective effects [37,73]. Therefore, for the elimination of MTX and cytoprotective purposes, “Bip 1”, “Bip 2”, and “Bip6” might have further beneficial effects in conjugation to CPG2.…”

MiR-1224 downregulation inhibits OGD/R-induced hippocampal neuron apoptosis through targeting Ku protein

“…Thus, those findings imply their potential roles in cell apoptosis. On the other hand, Ku70 can inhibit the N-terminal conformational changes of Bax and the transport from the cytosol to the mitochondria (Jensen et al 2019). In glioma cells, Ku70 can help prevent Bax from being transported to mitochondria to achieve anti-apoptosis and maintain tumor cell viability (Luo et al 2018).…”