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
| Autor: | Parthasarathy Muthuraman, Boglarka Racz, Konstantin Petrukhin, Arun Raja, András Váradi, Christopher L. Cioffi |
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| Rok vydání: | 2020 |
| Předmět: |
endocrine system
Amyloid Drug Evaluation Preclinical Pharmacology Crystallography X-Ray 01 natural sciences Article Lipofuscin Pathogenesis Macular Degeneration Mice 03 medical and health sciences chemistry.chemical_compound Biopolymers Tetramer Geographic Atrophy Drug Discovery Animals Humans Prealbumin Cytotoxic T cell 030304 developmental biology 0303 health sciences Retinol binding protein 4 Molecular Structure biology nutritional and metabolic diseases Retinal 0104 chemical sciences 010404 medicinal & biomolecular chemistry Transthyretin chemistry Drug Design biology.protein Molecular Medicine Retinol-Binding Proteins Plasma |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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