TY - JOUR

T1 - Oligomerization of Pharmaceutically Relevant Insulin Analogues for Varying Concentration and Salinity Revealed by Small-Angle X-ray Scattering

AU - Jensen, Grethe

AU - Rosenmejer, Katrine R.

AU - Huda, Pie

AU - Arleth, Lise

PY - 2021/9/6

Y1 - 2021/9/6

N2 - Two different insulin analogues, insulin degludec and lithocholyl insulin, were studied by small-angle X-ray scattering with respect to their self-assembly and interactions in solution at different concentrations of insulin and salt, NaCl. Very different behavior was observed for the two. Insulin degludec, linked to a hexadecanedioic acid, consistently formed di-hexamers, without any further oligomeric growth upon screening of electrostatic repulsions, indicating a stable di-hexamer unit without further oligomerization, as expected in the presence of phenol. The other insulin analogue, linked to the sterol lithocholic acid, formed n-hexamers with n ranging from 1 to 15, increasing with NaCl concentration and insulin concentration, indicating attractive forces in competition with the electrostatic repulsion and solution entropy. At the highest concentration of insulin and NaCl, a liquid crystal phase was observed, which has not previously been identified, featuring a quadratic structure organized into layers, which might hold interesting properties for pharmaceutical applications.

AB - Two different insulin analogues, insulin degludec and lithocholyl insulin, were studied by small-angle X-ray scattering with respect to their self-assembly and interactions in solution at different concentrations of insulin and salt, NaCl. Very different behavior was observed for the two. Insulin degludec, linked to a hexadecanedioic acid, consistently formed di-hexamers, without any further oligomeric growth upon screening of electrostatic repulsions, indicating a stable di-hexamer unit without further oligomerization, as expected in the presence of phenol. The other insulin analogue, linked to the sterol lithocholic acid, formed n-hexamers with n ranging from 1 to 15, increasing with NaCl concentration and insulin concentration, indicating attractive forces in competition with the electrostatic repulsion and solution entropy. At the highest concentration of insulin and NaCl, a liquid crystal phase was observed, which has not previously been identified, featuring a quadratic structure organized into layers, which might hold interesting properties for pharmaceutical applications.

KW - insulin degludec

KW - lithocholyl insulin

KW - SAXS

KW - self-assembly

KW - oligomerization

KW - NEUTRON-SCATTERING

KW - MECHANISM

KW - STABILIZATION

KW - PROTRACTION

KW - DEGLUDEC

U2 - 10.1021/acs.molpharmaceut.1c00164

DO - 10.1021/acs.molpharmaceut.1c00164

M3 - Journal article

C2 - 34351780

VL - 18

SP - 3272

EP - 3280

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 9

ER -