Sequence specificity of amylin-insulin interaction: a fragment-based insulin fibrillation inhibition study.

Authors:
Bhisma Narayan Ratha
Bhisma Narayan Ratha
Department of Biophysics
Ann Arbor | United States
Rajiv K Kar
Rajiv K Kar
Bose Institute
Kolkata | India
Sujan Kalita
Sujan Kalita
Laboratory of Peptide and Amyloid Research
Sourav Kalita
Sourav Kalita
Laboratory of Peptide and Amyloid Research
Achintya Singha
Achintya Singha
Indian Institute of Technology
India
Kanchan Garai
Kanchan Garai
Washington University School of Medicine
United States
Bhubaneswar Mandal
Bhubaneswar Mandal
Indian Institute of Technology Guwahati
India

Biochim Biophys Acta Proteins Proteom 2019 Apr 17;1867(4):405-415. Epub 2019 Jan 17.

Department of Biophysics, P-1/12 CIT Scheme VII (M), Kolkata 700054, India. Electronic address:

Subcutaneous insulin delivery serves as the major treatment for the ever-increasing spread of type II diabetes worldwide. However, long-term exposure to insulin results in local aggregates at the site of injection. This therapeutic concern accentuates the need to develop newer effective excipients to stabilize the insulin in pharmaceutical formulations. The fact that in normal physiological conditions, insulin interacts with the amylin hormone co-secreted from the pancreas, we targeted a peptide-mimetic approach based on the amylin sequence. The amylin-fibrillating core (NL6- NFGAIL from the human Islet Amyloid Poly-Peptide) and its derivative NFGAXL (NL6X, X = 2-aminobenzoic acid) were used as potential inhibitory peptides against insulin amyloidogenesis. The fibrillation kinetics in the presence of the inhibitors was studied using an array of biophysical and microscopic techniques. High-resolution NMR spectroscopy enabled probing of the inhibitory interaction at an atomic resolution. Our results highlight the potential of using the naturally evolved NL6 peptide as an effective inhibitor against insulin fibrillation.

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http://dx.doi.org/10.1016/j.bbapap.2019.01.007DOI Listing
April 2019
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