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Download fileDiscovery 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
journal contribution
posted on 17.09.2020, 10:03 authored by Christopher L. Cioffi, Parthasarathy Muthuraman, Arun Raja, Andras Varadi, Boglarka Racz, Konstantin PetrukhinAccumulation
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.
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Keywords
wild-type TTR misfoldingAMD patientsPreclinical Pharmacological Evaluationnongenetic diseasecytotoxic lipofuscin bisretinoidsgel-based assayage-related macular degenerationTTR amyloid formationPotential Therapyretinol binding protein 4TTR aggregationRetinol Binding Protein 4bisretinoid synthesisTTR tetramer destabilizationserum RBP 4 levelsStabilize Transthyretin TetramersRetinal bisretinoid synthesisRBP 4 antagonistsage-related comorbidityCommon Age-Related Comorbidities Ac...Scaffolding Hoppingmouse plasma RBP 4 levelsBispecific Antagonistsbispecific compounds