Protein engineering strategies with potential applications for altering clinically relevant cellular pathways at the protein level

ABSTRACT

All diseases can be fundamentally viewed as the result of malfunctioning cellular pathways. Protein engineering offers the potential to develop new tools that will allow these dysfunctional pathways to be better understood, in addition to potentially providing new routes to restore proper function. Here we discuss different approaches that can be used to change the intracellular activity of a protein by intervening at the protein level: targeted protein sequestration, protein recruitment, protein degradation, and selective inhibition of binding interfaces. The potential of each of these tools to be developed into effective therapeutic treatments will also be discussed, along with any major barriers that currently block their translation into the clinic.

KEYWORDS:

• Protein engineering
• cellular pathways
• protein degradation
• protein sequestration
• protein therapeutics
• pathway engineering

Financial & competing interests disclosure

The authors were supported by the Raymond and Beverly Sackler Institute for Biological, Physical and Engineering Sciences and NSF DMR 1307712, PHYS 1019147, PHYS 1305509, NIH CA016359. M Hinrichsen discloses T32 Biophysics training grant; Raymond and Beverly Sacker Institute for Biological, Physical and Engineering Sciences. C Oi discloses Yale Gruber Science Fellowship; Raymond and Beverly Sacker Institute for Biological, Physical and Engineering Sciences. L Regan discloses National Institutes of Health (NIH CA016359), National Science Foundation (PHYS 1305509/NSF DMR 1307712/PHYS 1019147); Raymond and Beverly Sacker Institute for Biological, Physical and Engineering Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.