Protein stability — An underappreciated but critical need for drug delivery systems

Cicerone, Marcus T.; Giri, Jyotsnendu; Shaked, Ze'ev; Roberts, Christopher J.

doi:10.1016/j.addr.2015.10.001

Cited by 10 publications

(10 citation statements)

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“…Dominant processes leading to protein degradation during storage include formation of aggregates, oxidation, deamination, and isomerization [128–130]. Transient or partial unfolding of otherwise soluble proteins can provide a pathway for aggregate formation based on strong covalent or noncovalent (hydrophobic, hydrogen bonding, and van der Waals) protein interactions.…”

Section: Protein Modifications and Strategies For Enhancing Pharmacolmentioning

confidence: 99%

Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment

Kintzing

Interrante

Cochran

2016

Trends in Pharmacological Sciences

165

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Protein-based therapeutics have been revolutionizing the oncology space since they first appeared in the clinic two decades ago. Unlike traditional small-molecule chemotherapeutics, protein biologics promote active targeting of cancer cells by binding to cell surface receptors and other markers specifically associated with or overexpressed on tumors versus healthy tissue. While the first approved cancer biologics were monoclonal antibodies, the burgeoning field of protein engineering is spawning research on an expanded range of protein formats and modifications that allow tuning of properties such as target binding affinity, serum half-life, stability, and immunogenicity. In this review, we highlight some of these strategies and provide examples of modified and engineered proteins under development as preclinical and clinicalstage drug candidates for treating cancer.

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Section: Protein Modifications and Strategies For Enhancing Pharmacolmentioning

confidence: 99%

Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment

Kintzing

Interrante

Cochran

2016

Trends in Pharmacological Sciences

165

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“…Subvisible particle, formed by the aggregation of protein monomers, has become a tough challenge for biopharmaceutical researchers. 1,2 Protein aggregation usually leads to lower biological potency, altered pharmacokinetic properties, reduced target binding affinity, and potentially life-threatening immunogenic responses. 3−5 To optimize the performance of therapeutic proteins, the manufacturing process, container quality, and storage conditions must be strictly controlled.…”

Section: ■ Introductionmentioning

confidence: 99%

“…3−5 To optimize the performance of therapeutic proteins, the manufacturing process, container quality, and storage conditions must be strictly controlled. 1,6,7 However, these measures alone cannot effectively inhibit protein aggregation since protein instability is intrinsic and comes from its structure or microconformation. 8,9 Because protein unfolding often initiates aggregation, improving the conformational stability is of paramount importance to retard or prevent the formation of aggregates.…”

Section: ■ Introductionmentioning

confidence: 99%

Protein Aggregation and Performance Optimization Based on Microconformational Changes of Aromatic Hydrophobic Regions

et al. 2018

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Protein aggregation is a key concern in biopharmaceutical development and manufacturing. There is growing interest in understanding how the changes in protein microconformation affect the aggregation behavior. This study selected several representative proteins and first manipulated microconformational changes of the aromatic hydrophobic regions of proteins, especially tryptophan residues, by using amine or guanidine additives. The effects of the interactions between the additives and proteins on the aromatic hydrophobic regions could be grouped into three categories: exposure to solvent, burial into core, and no change. The microconformational parameters of the tryptophan residue, including fluorescence peak position (λ), degree of hydrolysis, solvent accessible surface area ( SAS), and packing density ( Den), were obtained by steady-state fluorescence spectroscopy, proteolysis coupled with electrophoresis, and molecular dynamics simulation. Furthermore, the aggregation degrees of globular proteins with distinct surface aromatic hydrophobilities under mechanical stress were investigated. A strong correlation was observed between protein aggregation and the microconformational changes of the aromatic hydrophobic regions incurred by amine or guanidine additives. Protein aggregation was enhanced when the aromatic hydrophobic regions were exposed to the solvent but suppressed when the additives led to burial of the aromatic hydrophobic regions with lower-polarity microenvironment. These findings shed light on the relationship between protein aggregation and molecular conformation and paved way for future preformulation studies of therapeutic proteins.

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“…A central objective in the design of functional proteins is to tailor a scaffold structure that best supports the function encoded on a fraction of the template protein's surface. In addition to high activity levels, other criteria are pivotal for the successful deployment of a protein drug, such as activity half-life, folding rates, structural stability, solubility, and molecular weight 4,5 . These properties depend on a set of controllable protein parameters such as a protein's sequence, topology, and size.…”

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confidence: 99%

A topological refactoring design strategy yields highly stable granulopoietic proteins

Skokowa¹,

Alvarez

Coles

et al. 2022

Nat Commun

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Protein therapeutics frequently face major challenges, including complicated production, instability, poor solubility, and aggregation. De novo protein design can readily address these challenges. Here, we demonstrate the utility of a topological refactoring strategy to design novel granulopoietic proteins starting from the granulocyte-colony stimulating factor (G-CSF) structure. We change a protein fold by rearranging the sequence and optimising it towards the new fold. Testing four designs, we obtain two that possess nanomolar activity, the most active of which is highly thermostable and protease-resistant, and matches its designed structure to atomic accuracy. While the designs possess starkly different sequence and structure from the native G-CSF, they show specific activity in differentiating primary human haematopoietic stem cells into mature neutrophils. The designs also show significant and specific activity in vivo. Our topological refactoring approach is largely independent of sequence or structural context, and is therefore applicable to a wide range of protein targets.

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Protein stability — An underappreciated but critical need for drug delivery systems

Cited by 10 publications

References 0 publications

Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment

Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment

Protein Aggregation and Performance Optimization Based on Microconformational Changes of Aromatic Hydrophobic Regions

A topological refactoring design strategy yields highly stable granulopoietic proteins

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