Abstract
Diabetes-related neuropathy is a debilitating condition that may be averted if it can be detected early. One possible way this can be achieved at low cost is to utilise peptides to detect C-peptide, a biomarker of diabetic neuropathy. This depends on peptide-peptide co-assembly, which is currently in a nascent stage of intense study. Instead, we propose a bead-based triple-overlay combinatorial strategy that can preserve inter-residue information during the screening process for a suitable complementary peptide to co-assemble with C-peptide. The screening process commenced with a pentapeptide general library, which revealed histidine to be an essential residue. Further screening with seven tetrapeptide focused libraries led to a table of self-consistent peptide sequences that included tryptophan and lysine at high frequencies. Three complementary nonapeptides (9mer com-peptides), wpkkhfwgq (Trp-D), kwkkhfwgq (Lys-D), and KWKKHFWGQ (Lys-L) (as a negative control) were picked from this table for co-assembly studies with C-peptide. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) and circular dichroism (CD) spectroscopies were utilized to study inter-peptide interactions and changes in secondary structures respectively. ATR-FTIR studies showed that there is indeed inter-peptide interaction between C-peptide and the tryptophan residues of the 9mer com-peptides. CD studies of unaggregated and colloidal C-peptide with the 9mer com-peptides suggest that the extent of co-assembly of C-peptide with Trp-D is greatest, followed by Lys-D and Lys-L. These results are promising and indicate that the presented strategy is viable for designing and evaluating longer complementary peptides, as well as complementary peptides for co-assembly with other polypeptides of interest and importance. We discuss the possibility of designing complementary peptides to inhibit toxic amyloidosis with this approach.
Highlights
Proinsulin connecting peptide, in short C-peptide, is a 31-residue peptide that links the A and B chains of proinsulin
C-peptide was considered to be a side-product with insignificant bioactivity, but it was later discovered to influence a wide variety of physiological complications linked to diabetes, such as neuropathy, nephropathy, and encephalopathy [1]
Diabetic neuropathy is a debilitating condition in which the patient gradually loses sensation in the limbs due to progressive death of peripheral nerve cells
Summary
Proinsulin connecting peptide, in short C-peptide, is a 31-residue peptide that links the A and B chains of proinsulin. C-peptide was considered to be a side-product with insignificant bioactivity, but it was later discovered to influence a wide variety of physiological complications linked to diabetes, such as neuropathy, nephropathy, and encephalopathy [1]. Diabetic neuropathy is a debilitating condition in which the patient gradually loses sensation in the limbs due to progressive death of peripheral nerve cells. The loss of sensation makes the patient more susceptible to injuries, which could lead to amputation of the afflicted limb. Just as APL1b28 [4] and natriuretic peptides [5,6] can serve as biomarkers for Alzheimer’s disease and myocardial ischemia reperfusion injury respectively, it is desirable to monitor C-peptide concentration in the blood to permit timely intervention [7,8]
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