A current pharmacologic agent versus the promise of next generation therapeutics to ameliorate protein misfolding and/or aggregation diseases

Abstract

The list of protein aggregation-associated degenerative diseases is long and growing, while the portfolio of disease-modifying strategies is very small. In this review and perspective, we assess what has worked to slow the progression of an aggregation-associated degenerative disease, covering the underlying mechanism of pharmacologic action and what we have learned about the etiology of the transthyretin amyloid diseases and likely amyloidoses in general. Next, we introduce emerging therapies that should apply more generally to protein misfolding and/or aggregation diseases, approaches that rely on adapting the protein homeostasis or proteostasis network for disease amelioration.

Figure 1

Transthyretin structure and amyloidogenesis cascade. (A) Ribbon diagram depiction of the structure of homo-tetrameric TTR with T₄ occupying the ligand-binding site. (B) TTR amyloidogenic cascade. (C) Free energy diagram consistent with TTR aggregation.

Figure 2

Summary of key findings that led to a tafamidis-based kinetic stabilization strategy for the treatment and/or prevention of transthyretin-related amyloidoses. (A) Original liver transplantation-based strategy for replacing kinetically less stable heterotetrameric TTR with kinetically more stable wild type homotetrameric TTR for slowing the progression of familial amyloid polyneuropathy. (B) Line drawing of the tafamidis structure. (C) Structure of the (tafamidis)₂•TTR complex that dissociates slowly. (D) Mechanism of TTR stabilization by tafamidis.

Figure 3

Discovery path to tafamidis. Numerous observations summarized on this flow chart led to the discovery of tafamidis, its regulatory agency approval, and continuing biomarker discovery efforts.

Figure 4

The main decision to be made by the protein homeostasis, or proteostasis, network is to fold or refold a protein or degrade it by the ubiquitin proteasome system or by one of several lysosomal degradation pathways (autophagy is shown). While it is clear that intrinsically disordered proteins are degraded both by the proteasome and by the lysosome, it is less clear which proteostasis network components engage this class of proteins to keep them soluble and functional.