Here, we describe the molecular engineering of insulin icodec to achieve a plasma half-life of 196 h in humans, suitable for once-weekly subcutaneously administration. Insulin icodec is based on re-engineering of the ultra-long oral basal insulin OI338 with a plasma half-life of 70 h in humans. This systematic re-engineering was accomplished by (1) further increasing the albumin binding by changing the fatty diacid from a 1,18-octadecanedioic acid (C18) to a 1,20-icosanedioic acid (C20) and (2) further reducing the insulin receptor affinity by the B16Tyr → His substitution. Insulin icodec was selected by screening for long intravenous plasma half-life in dogs while ensuring glucose-lowering potency following subcutaneous administration in rats. The ensuing structure–activity relationship resulted in insulin icodec. In phase-2 clinical trial, once-weekly insulin icodec provided safe and efficacious glycemic control comparable to once-daily insulin glargine in type 2 diabetes patients. The structure–activity relationship study leading to insulin icodec is presented here.
An automated approach to peptaibols using microwave-assisted solid-phase peptide synthesis is demonstrated with a combination of HBTU and acid fluoride mediated couplings for normal and alpha,alpha-dialkylated amino acids, respectively. The method is utilized for the automated synthesis of several full-length peptaibols, including alamethicin, tylopeptin, ampullosporin, bergofungin, cervinin, trikoningin, trichogin, and peptaibolin, reducing both synthesis time and costs significantly as compared to other approaches. Furthermore, the use of noncommercially available reagents is minimized.
Recently, the first basal oral insulin (OI338) was shown to provide similar treatment outcomes to insulin glargine in a phase 2a clinical trial. Here, we report the engineering of a novel class of basal oral insulin analogues of which OI338, 10, in this publication, was successfully tested in the phase 2a clinical trial. We found that the introduction of two insulin substitutions, A14E and B25H, was needed to provide increased stability toward proteolysis. Ultralong pharmacokinetic profiles were obtained by attaching an albumin-binding side chain derived from octadecanedioic (C18) or icosanedioic acid (C20) to the lysine in position B29. Crucial for obtaining the ultralong PK profile was also a significant reduction of insulin receptor affinity. Oral bioavailability in dogs indicated that C18-based analogues were superior to C20-based analogues. These studies led to the identification of the two clinical candidates OI338 and OI320 (10 and 24, respectively).
The nonproteinogenic, C(α)-tetrasubstituted, helicogenic, chiral α-amino acid isovaline (Iva) is remarkably spread in the biosphere. Together with its achiral, lower homolog α-aminoisobutyric acid (Aib), it represents a characteristic marker of a class of naturally occurring peptide antibiotics, for which the acronym "peptaibiotics" became established. In these peptides, Iva occurs as the (S)-(= L) or the (R)-(= D) enantiomer, but peptide sequences containing both Iva enantiomers are also common. Here, we applied our recently developed (1)H-NMR method, which enables the nondestructive assignment of the configuration of each Iva residue in a peptide of known helical screw sense, to natural and synthetic peptaibiotics. Our method proved to be generally applicable and provided evidence that, in the peptaibiotic bergofungin A, the Iva(12) configuration is (R) and not (S) as reported previously. Moreover, we extended our NMR method by including a (13)C-NMR parameter. A statistical analysis of the preferred main- and side-chain conformations of the Iva residues in peptides, performed based on their published X-ray diffraction structures, allowed us to provide a sound rationale to the NMR criteria exploited to establish the configuration of this amino acid.
Bacterial resistance to classical antibiotics is a serious medical problem, which continues to grow. Small antimicrobial peptides represent a potential solution and are increasingly being developed as novel therapeutic agents. Many of these peptides owe their antibacterial activity to the formation of trans-membrane ion-channels resulting in cell lysis. However, to further develop the field of peptide antibiotics, a thorough understanding of their mechanism of action is needed. Alamethicin belongs to a class of peptides called peptaibols and represents one of these antimicrobial peptides. To examine the dynamics of assembly and to facilitate a thorough structural evaluation of the alamethicin ion-channels, we have applied click chemistry for the synthesis of templated alamethicin multimers covalently attached to cyclodextrin-scaffolds. Using oriented circular dichroism, calcein release assays, and single-channel current measurements, the α-helices of the templated multimers were demonstrated to insert into lipid bilayers forming highly efficient and remarkably stable ion-channels.
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