Details

Autor(en) / Beteiligte

• Crook, Zachary R.
• Nairn, Natalie W.
• Olson, James M.

Titel

Miniproteins as a Powerful Modality in Drug Development

Ist Teil von

• Trends in biochemical sciences (Amsterdam. Regular ed.), 2020-04, Vol.45 (4), p.332-346

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Miniproteins are a diverse group of protein scaffolds characterized by small (1–10 kDa) size, stability, and versatility in drug-like roles. Coming largely from native sources, they have been widely adopted into drug development pipelines. While their structures and capabilities are diverse, the approaches to their utilization share more similarities with each other than with more widely used modalities (e.g., antibodies or small molecules). In this review, we highlight recent advances in miniprotein-based approaches to otherwise poorly addressed clinical needs, including structure-based and functional characterization. We also summarize their unique screening strategies and pharmacology considerations. Through a greater understanding of the unique properties that make them attractive for drug design, miniproteins can be effectively utilized against targets that are intractable by other approaches. Therapeutics based on miniprotein scaffolds can have antibody-like affinity and functionality while avoiding some of the liabilities of larger scaffolds, such as poor tissue or cell penetration, protease and reduction sensitivity, complex manufacturing and characterization, or (for antibodies) reliance on targets of poor host homology.Among miniproteins, three categories (hydrophobic core, cystine-reinforced, and chemically stabilized) emerge with distinct biochemical and biophysical characteristics but similar utility.Most screening campaigns use a variant of surface display, although chemical conjugation can be utilized if necessary.Miniprotein candidates that do not naturally have favorable serum half-life, cell penetration, or protease resistance properties can often be engineered through evolution, genetic fusion, or chemical modification for these characteristics.