Discovery of Bispecific Antagonists of Retinol Binding Protein 4 That Stabilize Transthyretin Tetramers: Scaffolding Hopping, Optimization, and Preclinical Pharmacological Evaluation as a Potential Therapy for Two Common Age-Related Comorbidities

Christopher L Cioffi, Parthasarathy Muthuraman, Arun Raja, Andras Varadi, Boglarka Racz, Konstantin Petrukhin

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Accumulation of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex. We previously identified selective RBP4 antagonists that dissociate circulating RBP4-TTR-retinol complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. However, the release of TTR by selective RBP4 antagonists may be associated with TTR tetramer destabilization and, potentially, TTR amyloid formation. We describe herein the identification of bispecific RBP4 antagonist-TTR tetramer kinetic stabilizers. Standout analogue (±)-44 possesses suitable potency for both targets, significantly lowers mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based assay. This new class of bispecific compounds may be especially important as a therapy for dry AMD patients who have another common age-related comorbidity, senile systemic amyloidosis, a nongenetic disease associated with wild-type TTR misfolding.

Original languageEnglish
Pages (from-to)11054-11084
Number of pages31
JournalJournal of Medicinal Chemistry
Volume63
Issue number19
DOIs
StatePublished - 8 Oct 2020
Externally publishedYes

Keywords

  • Animals
  • Biopolymers/chemistry
  • Crystallography, X-Ray
  • Drug Design
  • Drug Evaluation, Preclinical
  • Geographic Atrophy/drug therapy
  • Humans
  • Macular Degeneration/drug therapy
  • Mice
  • Molecular Structure
  • Prealbumin/chemistry
  • Retinol-Binding Proteins, Plasma/antagonists & inhibitors

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