Defining Structure‐Function Relationships of Amphiphilic Excipients Enables Rational Design of Ultra‐Stable Biopharmaceuticals

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Biopharmaceuticals are the fastest-growing class of drugs in healthcare industry, but their global reach is severely limited by propensity for rapid aggregation. Currently, surfactant excipients such as polysorbates and poloxamers used to prevent protein aggregation, which significantly extends shelf-life. Unfortunately, these themselves unstable, oxidizing rapidly into 100s distinct compounds, some cause severe adverse events patients. Here, highly stable, well-defined, modular nature amphiphilic polyacrylamide-derived leveraged isolate key mechanisms responsible excipient-mediated stabilization. With a library compositionally identical structurally excipients, new property quantified, compositional dispersity, that excipient performance utilized this rationally design ultra-stable increase stability notoriously unstable biopharmaceutical, monomeric insulin, an order magnitude. This comprehensive generalizable understanding structure-function relationships represents paradigm shift formulation biopharmaceuticals, moving away from trial-and-error screening approaches toward rational design.

Language: Английский

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Selective Depolymerization for Sculpting Polymethacrylate Molecular Weight Distributions

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Chain-end reactivation of polymethacrylates generated by reversible-deactivation radical polymerization (RDRP) has emerged as a powerful tool for triggering depolymerization at significantly milder temperatures than those traditionally employed. In this study, we demonstrate how the facile poly(butyl methacrylate) (PBMA) can be leveraged to selectively skew molecular weight distribution (MWD) and predictably alter viscoelastic properties blended PBMA mixtures. By mixing polymers with thermally active chain ends different weights inactive ends, MWD blends skewed high or low selective depolymerization. This approach leads counterintuitive principle "destructive strengthening" material. Finally, demonstrate, proof concept, encryption information within polymer mixtures linking Morse code MWDs before after depolymerization, allowing encoding data synthetic macromolecules.

Language: Английский

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Ultrafast Thermal RAFT Depolymerization at Higher Solid Contents

ACS Macro Letters, Journal Year: 2025, Volume and Issue: unknown, P. 235 - 240

Published: Feb. 10, 2025

Although thermal solution RAFT depolymerization has recently emerged as an efficient chemical recycling methodology, current approaches require specialized solvents (i.e., dioxane), typically suffer from extended reaction times, and operate exclusively under highly dilute conditions 5 mM repeat unit concentration). To circumvent these limitations, a commercial radical initiator is introduced to kinetically untrap the promote chain-end activation. By varying concentration, remarkable rate acceleration (up 72 times faster) can be observed, enabling completion of within min. Notably, 20-fold increase in concentration did not appreciably compromise final yield, while very high percentages monomer could recovered wide range solvents, including dimethyl sulfoxide, anisole, xylene, acetonitrile, toluene, trichlorobenzene. Our findings only offer intriguing mechanistic aspects, but also significantly expand scope applications depolymerization.

Language: Английский

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Tailoring polymer architectures to drive molecular sieving in protein-polymer hybrids

Sustainable Chemistry and Pharmacy, Journal Year: 2025, Volume and Issue: 45, P. 101988 - 101988

Published: March 14, 2025

Language: Английский

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Elucidating structure-function relationships of amphiphilic copolymer excipients to enhance the stability of biopharmaceuticals

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 19, 2024

Biopharmaceuticals are the fastest growing class of drugs in healthcare industry, but their global reach is severely limited by propensity for rapid aggregation. Currently, surfactant excipients such as polysorbates and poloxamers used to prevent protein aggregation, which significantly extends shelf-life. Unfortunately, these themselves unstable, oxidizing rapidly into 100s distinct compounds, some cause severe adverse events patients. Here, we leverage highly stable, well-defined, modular nature amphiphilic polyacrylamide-derived isolate key mechanisms responsible excipient-mediated stabilization. With a library compositionally identical structurally copolymers, quantify multiple relationships between polymer properties fundamental phenomena rationally design new ultra-stable excipients, increasing stability notoriously unstable biopharmaceutical, monomeric insulin, an order magnitude. This comprehensive generalizable understanding excipient structure-function represents paradigm shift formulation biopharmaceuticals, moving away from trial-and-error screening approaches towards rational design.

Language: Английский

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Polymers for Disrupting Protein–Protein Interactions: Where Are We and Where Should We Be?

Biomacromolecules, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Protein-protein interactions (PPIs) are central to the cellular signaling and regulatory networks that underlie many physiological pathophysiological processes. It is challenging target PPIs using traditional small molecule or peptide-based approaches due frequent lack of well-defined binding pockets at large flat PPI interfaces. Synthetic polymers offer an opportunity circumvent these challenges by providing unparalleled flexibility in tuning their physiochemical properties achieve desired properties. In this review, we summarize current state field pertaining polymer-protein solution, highlighting various polyelectrolyte systems, tunable parameters, characterization. We provide outlook on how architectures can be improved incorporating sequence control, foldability, machine learning mimic proteins every structural level. Advances directions will enable design more specific protein-binding effective strategy for targeting dynamic proteins, such as intrinsically disordered proteins.

Language: Английский

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Sequence‐sensitivity in functional synthetic polymer properties

Angewandte Chemie, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 8, 2024

Abstract Recently, a new class of synthetic methyl methacrylate‐based random heteropolymers (MMA‐based RHPs) has displayed protein‐like properties. Their function appears to be insensitive the precise sequence. Here, through atomistic molecular dynamics simulation, we show that there are universal features MMA‐based RHPs sequence, and mostly depend on overall composition. In particular, find “fold” into globules with heterogeneous hydration patterns. However, insensitivity sequence identity observed in dramatically changes when substitute backbone architecture acrylate or replace oxygen atom side chain nitrogen (methacrylamide acrylamide). such scenarios, contributes significantly compactness monomers. Using principal component analysis an intersection‐over‐union based index, demonstrate different sequences may not overlap property space, meaning their properties controlled by rather than fixed We further investigate sequence‐insensitive capability as previously reported bacterial phospholipase OmpLA stabilization heterodimerization. As experimentally observed, polymers enhance stability reliably its native bilayer environment. The design provides alternative protein‐mimetic biomaterials is orthogonal sequence‐structure‐function paradigm proteins.

Language: Английский

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Sequence‐sensitivity in functional synthetic polymer properties

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 8, 2024

Recently, a new class of synthetic methyl methacrylate-based random heteropolymers (MMA-based RHPs) has displayed protein-like properties. Their function appears to be insensitive the precise sequence. Here, through atomistic molecular dynamics simulation, we show that there are universal features MMA-based RHPs sequence, and mostly depend on overall composition. In particular, find "fold" into globules with heterogeneous hydration patterns. However, insensitivity sequence identity observed in dramatically changes when substitute backbone architecture acrylate or replace oxygen atom side chain nitrogen (methacrylamide acrylamide). such scenarios, contributes significantly compactness monomers. Using principal component analysis an intersection-over-union based index, demonstrate different sequences may not overlap property space, meaning their properties controlled by rather than fixed We further investigate sequence-insensitive capability as previously reported bacterial phospholipase OmpLA stabilization heterodimerization. As experimentally observed, polymers enhance stability reliably its native bilayer environment. The design provides alternative protein-mimetic biomaterials is orthogonal sequence-structure-function paradigm proteins.

Language: Английский

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