Autonomously folded α-helical lockers promote RNAi*

DOI: 10.1038/srep35012

Authors: Christian P. E. Guyader (University of Cambridge; National Physical Laboratory) , Baptiste Lamarre (National Physical Laboratory) , Emiliana De Santis (National Physical Laboratory) , James E. Noble (National Physical Laboratory) , Nigel K. Slater (University of Cambridge) , Maxim G. Ryadnov (National Physical Laboratory)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 6

State: Published (Approved)
Published: October 2016
Diamond Proposal Number(s): 10068

Abstract: RNAi is an indispensable research tool with a substantial therapeutic potential. However, the complete transition of the approach to an applied capability remains hampered due to poorly understood relationships between siRNA delivery and gene suppression. Here we propose that interfacial tertiary contacts between α-helices can regulate siRNA cytoplasmic delivery and RNAi. We introduce a rationale of helical amphipathic lockers that differentiates autonomously folded helices, which promote gene silencing, from helices folded with siRNA, which do not. Each of the helical designs can deliver siRNA into cells via energy-dependent endocytosis, while only autonomously folded helices with pre-locked hydrophobic interfaces were able to promote statistically appreciable gene silencing. We propose that it is the amphipathic locking of interfacing helices prior to binding to siRNA that enables RNAi. The rationale offers structurally balanced amphipathic scaffolds to advance the exploitation of functional RNAi.

Journal Keywords: Drug delivery; Protein design

Subject Areas: Medicine, Biology and Bio-materials


Instruments: B23-Circular Dichroism

Documents:
srep35012.pdf