AVLX-144 - a best in class neuroprotectant

Avilex Pharma is developing a pipeline of novel inhibitors of PDZ domain proteins to target unmet medical needs. Our lead candidate – AVLX-144 – is a dimeric peptide-like drug candidate for the treatment of acute ischemic stroke, which targets the intracellular scaffolding protein, postsynaptic density protein 95 (PSD-95). AVLX-144 is an extensively optimized dimeric PSD-95 inhibitor, and a clinical lead candidate for the treatment of acute conditions such as subarachnoid hemorrhage (SAH) and acute ischemic stroke (AIS).

PSD-95 bridges the glutamate receptor subtype, the N-methyl-D-aspartate (NMDA) receptor and neuronal nitric oxide synthase (nNOS) via its two PDZ domains. This is specifically exploited by AVLX-144, which binds to both these PDZ domains in PSD-95 simultaneously. The specific design of AVLX-144 provides several key advantages such as exceptionally high affinity to PSD-95, increased stability and enhanced in vivo neuroprotective properties.

Literature

Bach, A., C.N. Chi, G.F. Pang, L. Olsen, A.S. Kristensen, P. Jemth and K. Strømgaard, Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95/ NMDA receptor interaction. Angew. Chem. Int. Ed. 48: 9685-9689 (2009)

Bach, A., B.H. Clausen, M. Møller, B. Vestergaard, C.N. Chi, A. Round, P.L. Sørensen, K.B. Nissen, J.S. Kastrup, M. Gajhede, P. Jemth, A.S. Kristensen, P. Lundström, K.L. Lambertsen and K. Strømgaard. A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. Proc. Natl. Acad. Sci. USA 109: 3317-3322 (2012)

K. Kucharz, I. S. Rasmussen, A. Bach, K. Strømgaard, M. Lauritzen, PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarization in cortical spreading depression, J. Cereb. Blood Flow Metab. 37: 1820-1828 (2017)

A. Bach, B. H. Clausen, L. K. Kristensen, M. G. Andersen, D. G. Ellman, P. B. L. Hansen, H. Hasseldam, M. Heitz, D. Özcelik, E. J. Tuck, M. V. Kopanitsa, S. G. N. Grant, K. Lykke-Hartmann, F. F. Johansen, K. L. Lambertsen, K. Strømgaard, Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor. Neuropharmacology, 150: 100-111 (2019)

M. I. Rosenbaum, L.S. Clemmensen, D. S. Bredt, B. Bettler, K. Strømgaard, Targeting receptor complexes: A new dimension in drug discovery, Nature Rev. Drug Discov. 19: 884–901 (2020).