Therapeutic peptides: Targeting the mitochondrion to modulate apoptosis

Abstract

For many years, medical drug discovery has extensively exploited peptides as lead compounds. Currently, novel structures of therapeutic peptides are derived from active pre-existing peptides or from high-throughput screening, and optimized following a rational drug design approach. Molecules of interest may prove their ability to influence the disease outcome in animal models and must respond to a set of criteria based on toxicity studies, ease of administration, the cost of their synthesis, and logistic for clinical use to validate it as a good candidate in a therapeutic perspective. This applies to the potential use of peptides to target one central intracellular organelle, the mitochondrion, to modulate (i.e. activate or prevent) apoptosis. Putative mitochondrial protein targets and the strategies already elaborated to correct the defects linked to these proteins (overexpression, inactivation, mutation..., etc.) are described, and recent advances that led or may lead to the conception of therapeutic peptides via a specific action on these mitochondrial targets in the future are discussed.

Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead

“…This complex is located at contact sites between the mitochondrial inner and outer membranes (Ott et al 2007). Three MPTP components involve in favoring the closed or the open state of MPTP, respectively, and thus enabling a tight regulation of the mitochondria-mediated apoptosis (Jacotot et al 2006). However, the precise molecular mechanisms underlying Pb-induced mitochondrial pathway of apoptosis in primary cultures of rPT cells with regard to MPT regulation and roles of three MPTP components are largely unknown.…”

“…Thus, mitochondria are known as a key mediator of intrinsic apoptotic cell death. Furthermore, it is important to note that mitochondrial permeability transition (MPT) is a determinant factor in activation of mitochondrial pathway of apoptosis under oxidative stress conditions (Jacotot et al 2006), which could result in the loss of the mitochondrial membrane potential (ΔΨm) and subsequent mitochondrial impairment (Gupta et al 2009). In our previous study, Pb could induce the depletion of ΔΨm in rPT cells, which enable us to think whether MPT would play a part in Pbinduced apoptosis in rPT cells.…”

Bax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells

“…In vitro assessment of mitochondrial parameters (swelling and  m loss) was performed on liver mitochondria as previously described (Jacotot et al, 2006). Mitochondrial membrane potential was measured using the fluorescent dye MitoTracker Red (Molecular Probes), which emits fluorescence in cells with an intact  m .…”

Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of αVβ3-expressing endothelial cells

“…10,11 Indeed, the permeability transition pore (PTP) is assumed to be due to the formation of a dynamic multiprotein complex at outer and inner mitochondrial membrane contact sites. 13 The exact composition of the PTP is still unknown but appears to contain VDAC in the outer membrane and is regulated by ANT in the inner membrane, and cyclophilin D (the target for cyclosporin A, CsA), located in the matrix.…”