Chapter 10
Development of Peptide-Based PDZ Domain Inhibitors
Dominik J. Essig, Javier R. Balboa, and Kristian Strømgaard
Abstract
Over the past decades, peptide-based drugs have gained increasing interest in a wide range of treatment
applications, primarily because of high potency and selectivity, as well as good efficacy, tolerability, and safety
often achieved with peptides. Attempts to target postsynaptic density protein of 95 (PSD-95) PSD-95/
Discs large/Zonula occludens-1 (PDZ) domains, which mediate the formation of a ternary complex with
the N-methyl-D-aspartate (NMDA) receptor and neuronal nitric oxide synthase (nNOS) responsible for
excitotoxicity in ischemic stroke, by high-affinity small molecules have failed in the past. In this chapter, we
focus on the discovery of peptide-based drugs targeting PSD-95, using AVLX-144 as an example, from the
synthesis, over binding assays to its target, to further in vitro experiments based on the development of
AVLX-144, a potential stroke treatment, which is planned to enter clinical trials in 2020.
Key words PDZ domains, Protein–protein interactions, Inhibition, Stroke, AVLX-144
1 Introduction
Protein–protein interactions (PPIs) are highly abundant regulatory
mechanism in biological systems, which mediate a broad range of
cellular processes, including signal transduction, cellular communication, metabolism, gene expression, and membrane transport.
Hence, dysfunction or alterations of PPIs are linked to various
diseases states, and inhibition of PPIs possesses enourmous opportunities in drug discovery [1–3]. Many PPIs are mediated by
specialized protein domains, one of the most abundant being postsynaptic density protein-95/Discs large/Zonula occludens-1
(PDZ) domains.
PDZ domains consist of 80–90 amino acids and are present in
great number in multicellular organisms; in humans 267 different
PDZ domains are found in over 150 different proteins [4, 5]. PDZ
domains are usually part of scaffold and adaptor proteins involved
in the assembly of cellular signaling complexes, typically by recognizing the C-terminal of their interacting partners. Inhibition of
Jean-Paul Borg (ed.), PDZ Mediated Interactions: Methods and Protocols, Methods in Molecular Biology, vol. 2256,
https://doi.org/10.1007/978-1-0716-1166-1_10, © Springer Science+Business Media, LLC, part of Springer Nature 2021
157
Development of Peptide-Based PDZ Domain Inhibitors
Dominik J. Essig, Javier R. Balboa, and Kristian Strømgaard
Abstract
Over the past decades, peptide-based drugs have gained increasing interest in a wide range of treatment
applications, primarily because of high potency and selectivity, as well as good efficacy, tolerability, and safety
often achieved with peptides. Attempts to target postsynaptic density protein of 95 (PSD-95) PSD-95/
Discs large/Zonula occludens-1 (PDZ) domains, which mediate the formation of a ternary complex with
the N-methyl-D-aspartate (NMDA) receptor and neuronal nitric oxide synthase (nNOS) responsible for
excitotoxicity in ischemic stroke, by high-affinity small molecules have failed in the past. In this chapter, we
focus on the discovery of peptide-based drugs targeting PSD-95, using AVLX-144 as an example, from the
synthesis, over binding assays to its target, to further in vitro experiments based on the development of
AVLX-144, a potential stroke treatment, which is planned to enter clinical trials in 2020.
Key words PDZ domains, Protein–protein interactions, Inhibition, Stroke, AVLX-144
1 Introduction
Protein–protein interactions (PPIs) are highly abundant regulatory
mechanism in biological systems, which mediate a broad range of
cellular processes, including signal transduction, cellular communication, metabolism, gene expression, and membrane transport.
Hence, dysfunction or alterations of PPIs are linked to various
diseases states, and inhibition of PPIs possesses enourmous opportunities in drug discovery [1–3]. Many PPIs are mediated by
specialized protein domains, one of the most abundant being postsynaptic density protein-95/Discs large/Zonula occludens-1
(PDZ) domains.
PDZ domains consist of 80–90 amino acids and are present in
great number in multicellular organisms; in humans 267 different
PDZ domains are found in over 150 different proteins [4, 5]. PDZ
domains are usually part of scaffold and adaptor proteins involved
in the assembly of cellular signaling complexes, typically by recognizing the C-terminal of their interacting partners. Inhibition of
Jean-Paul Borg (ed.), PDZ Mediated Interactions: Methods and Protocols, Methods in Molecular Biology, vol. 2256,
https://doi.org/10.1007/978-1-0716-1166-1_10, © Springer Science+Business Media, LLC, part of Springer Nature 2021
157