Selectivity and efficacy in TRAIL-mediated apoptosis

Promotie: dhr. C.R.R. dos Reis, 14.45 uur, Academiegebouw, Broerstraat 5, Groningen

Proefschrift: Selectivity and efficacy in TRAIL-mediated apoptosis

Promotor(s): prof.dr. W.J. Quax

Faculteit: Wiskunde en Natuurwetenschappen

Contact: Carlos Reis, tel. 050-363 3039, e-mail: c.r.reis@rug.nl

Selectivity and efficacy in TRAIL-mediated apoptosis

Carlos Reis investigated Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a cytokine from the TNF superfamily. TRAIL has gained much attention due to the demonstration of its therapeutic potential as a tumour-specific apoptosis inducer. TRAIL has been shown to induce apoptosis selectively in many tumour cell lines without affecting normal cells and tissues, making TRAIL itself as well as possible agonists for the two human death receptors of TRAIL, DR4 and DR5, promising novel biotherapeutics for cancer therapy.

The promiscuity of TRAIL and the ability of decoy receptors to block apoptosis is reason to assume that introduction of receptor specificity increases the apoptotic potential of TRAIL. Furthermore, studies suggest that in many cancer cells only one of the two death-inducing TRAIL receptors is functional. Computational Protein Design is a powerful tool that allows improvement of protein properties such as stability, receptor specificity and immunogenicity. By using this tool Reis was able to calculate changes in receptor binding energy upon mutation in the binding interface of TRAIL and receptor, by using rotamer libraries and take into account movement of neighbouring residues. With this method, mutations can be designed that result in significant changes in binding energy, i.e., better binding to the selected receptor and/or lower binding to the other receptors. The work described in Reis’s thesis is aimed at the design and characterization of novel human recombinant TRAIL variants for increased induction of apoptosis in cancer cells as well as the kinetic elucidation of the interaction between TRAIL and its death receptors.