Evaluation of the effect of d-amino acid incorporation into amyloid-reactive peptides

Abstract

BackgroundSystemic amyloidoses comprise diseases characterized by the deposition of proteinaceous material known as amyloid. Currently, without performing multiple biopsies, there is no way to ascertain the extent of amyloid deposition in patients—a critical piece of information that informs prognosis and therapeutic strategies. We have developed pan-amyloid-targeting peptides for imaging amyloid and recently have adapted these for use as pre-targeting agents in conjunction with immunotherapy. Incorporation of d-amino acids in these peptides may enhance serum half-life, which is an important characteristic of effective peptide therapeutics. Herein, we assess the effects of partial incorporation of d-amino acids into the amyloidophilic peptide p5 on in vivo amyloid reactivity.MethodsPeptides, referred to as AQAp5(d), aqap5, and AQAp5, were radiolabeled with iodine-125 and the tissue biodistribution (% injected dose/gram) measured in healthy mice at multiple time points post-injection. Microscopic distribution of the peptides was further visualized using microautoradiography (ARG). Peptides aqap5 and AQAp5 were injected into healthy and amyloid-laden mice and evaluated by using SPECT/CT imaging at 1, 4 and 24 h post injection.ResultsBiodistribution data and ARG revealed persistent retention of [125I]AQAp5(d) in the liver and kidneys of healthy mice for at least 24 h. In contrast, peptides [125I]aqap5 and [125I]AQAp5 did not bind these organs and was significantly lower than [125I]AQAp5(d) at 24 h post injection (p < 0.0001). SPECT/CT imaging of amyloid-laden mice revealed accumulation of both [125I]aqap5 and [125I]AQAp5 in amyloid-affected organs; whereas, in healthy mice, [125I]aqap5 was observed in the kidneys and liver at early time points, and free radioiodide liberated during catabolism of [125I]AQAp5 was seen in the stomach and thyroid. Autoradiography confirmed that both [125I]aqap5 and [125I]AQAp5 peptides specifically bound amyloid with no off-target binding to healthy organs.ConclusionIncorporation of d-amino acids in amyloid-binding regions of amyloidophilic peptides resulted in off-target binding; however, N-terminus placement retained amyloid-specificity and evasion of deiodinases. Peptide aqap5, or similar reagents, may prove useful in novel immunotherapy strategies as well as for imaging renal, gastric and pancreatic amyloidosis.Electronic supplementary materialThe online version of this article (10.1186/s12967-017-1351-0) contains supplementary material, which is available to authorized users.

Mechanistic insights into the pH-dependent membrane peptide ATRAM

“…Similarly, high activity was observed in the thyroid and stomach. As radiolabeled peptide was injected intravenously, it would be eventually taken up by the kidneys and undergo catabolism and dehalogenation 55,56 . As shown in Fig.…”

Stereoselectivity of Interaction of Nonsteroidal Anti-Inflammatory Drug S-Ketoprofen with L/D-Tryptophan in Phospholipid Membranes

“…Another hypothesis explaining the self-association of Aβ is connected with the accumulation of D-amino acids in the Aβ structure [ 13 ]. Although, D-amino acids are studied as potential therapeutic agents against Alzheimer’s disease [ 14 , 15 ]. All D-peptides are considered potential agents breaking the self-association of L-rich Aβ [ 16 ].…”

Single-conformation spectroscopy of cold, protonated DPG-containing peptides: switching β-turn types and formation of a sequential type II/II′ double β-turn

“…10,11 Therapeutic peptides are designed with these properties in mind to enhance the efficacy and selectivity of pharmaceuticals. 11,12 Of all the D-amino acids, the effect D-proline has on secondary structure is one of the most significant. Substitution of L-proline with D-proline is known to greatly stabilize b-turn formation in peptides.…”