TY - JOUR AB - Small interfering RNA (siRNA) has emerged as a valuable tool to address RNA interference (RNAi) to modulate gene expression also in therapy. However, challenges such as inefficient cell targeting and rapid degradation in biological systems have limited its success. To address these issues, the development of a receptor-specific shuttle system represents a promising solution. [F7,P34]-NPY analogues were modified by solid-phase peptide synthesis, enabling non-covalent conjugation with siRNA. This modification yielded an efficient siRNA vehicle capable of binding and transporting its cargo into target cells without adversely affecting receptor activation or cell viability. Mass spectrometry and gel shift assays confirmed successful and stable siRNA binding under various conditions. Microscopy experiments further demonstrated the co-internalization of labeled peptides and siRNA in Hepa1c1 cells, highlighting the stability of the complex. In vitro quantitative RT-PCR experiments, targeting the TSC22D4 gene to normalize systemic glucose homeostasis and insulin resistance, revealed a functional peptide-based siRNA shuttle system with the ability to decrease mRNA expression to approximately 40%. These findings strengthen the potential of receptor-specific siRNA shuttle systems as efficient tools for gene therapy that offer a possibility for reducing side effects. AU - Schenk, M.* AU - Mörl, K.* AU - Herzig, S. AU - Beck-Sickinger, A.G.* C1 - 70616 C2 - 55771 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Targeted modulation of gene expression through receptor-specific delivery of small interfering RNA peptide conjugates. JO - J. Pept. Sci. PB - Wiley PY - 2024 SN - 1075-2617 ER - TY - JOUR AB - It is undeniably one of the greatest findings in biology that (with some very minor exceptions) every cell in the body possesses the whole genetic information needed to generate a complete individual. Today, this concept has been so thoroughly assimilated that we struggle to still see how surprising this finding actually was: all cellular phenotypes naturally occurring in one person are generated from genetic uniformity, and thus are per definition epigenetic. Transcriptional mechanisms are clearly critical for developing and protecting cell identities, because a mis-expression of few or even single genes can efficiently induce inappropriate cellular programmes. However, how transcriptional activities are molecularly controlled and which of the many known epigenomic features have causal roles remains unclear. Today, clarification of this issue is more pressing than ever because profiling efforts and epigenome-wide association studies (EWAS) continuously provide comprehensive datasets depicting epigenomic differences between tissues and disease states. In this commentary, we propagate the idea of a widespread follow-up use of epigenome editing technology in EWAS studies. This would enable them to address the questions of which features, where in the genome, and which circumstances are essential to shape development and trigger disease states. AU - DiMarchi, R.D.* AU - Mayer, J.P.* AU - Gelfanov, V.M.* AU - Tschöp, M.H. C1 - 52746 C2 - 44434 CY - 6-9 Carlton House Terrace, London Sw1y 5ag, England TI - Max Bergmann award lecture: Macromolecular medicinal chemistry as applied to metabolic diseases. JO - J. Pept. Sci. VL - 24 IS - 1 PB - Royal Soc PY - 2018 SN - 1075-2617 ER - TY - JOUR AB - The nematocyst walls of Hydra are formed by proteins containing small cysteine-rich domains (CRDs) of ~25 amino acids. The first CRD of nematocyst outer all antigen (NW1) and the C-terminal CRD of minicollagen-1 (Mcol1C) contain six cysteines at identical sequence positions, however adopt different disulfide bonded structures. NW1 shows the disulfide connectivities C2-C14/C6-C19/C10-C18 and Mcol1C C2-C18/C6-C14/C10-C19. To analyze if both show structural preferences in the open, non-disulfide bonded form, which explain the formation of either disulfide connectivity pattern, molecular dynamics (MD) simulations at different temperatures were performed. NW1 maintained in the 100-ns MD simulations at 283 K a rather compact fold that is stabilized by specific hydrogen bonds. The Mcol1C structure fluctuated overall more, however stayed most of the time also rather compact. The analysis of the backbone Φ/ψ angles indicated different turn propensities for NW1 and Mcol1C, which mostly can be explained based on published data about the influence of different amino acid side chains on the local backbone conformation. Whereas a folded precursor mechanism may be considered for NW1, Mcol1C may fold according to the quasi-stochastic folding model involving disulfide bond reshuffling and conformational changes, locking the native disulfide conformations. The study further demonstrates the power of MD simulations to detect local structural preferences in rather dynamic systems such as the open, non-disulfide bonded forms of NW1 and Mcol1C, which complement published information from NMR backbone residual dipolar couplings. Because the backbone structural preferences encoded by the amino acid sequence embedding the cysteines influence which disulfide connectivities are formed, the data are generally interesting for a better understanding of oxidative folding and the design of disulfide stabilized therapeutics. AU - Dames, S.A. C1 - 43856 C2 - 36620 CY - Hoboken SP - 480-494 TI - One short cysteine-rich sequence pattern - two different disulfide-bonded structures - a molecular dynamics simulation study. JO - J. Pept. Sci. VL - 21 IS - 6 PB - Wiley-blackwell PY - 2015 SN - 1075-2617 ER - TY - JOUR AB - The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Unfortunately, leptin monotherapy is insufficient in reversing obesity in rodents or humans. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. However, as the uniqueness of this combination therapy remains unclear, we assessed whether co-administration of leptin with other weight loss-inducing hormones equally restores leptin responsiveness in diet-induced obese (DIO) mice. Accordingly, we report here the design and characterization of a series of site-specifically enhanced leptin analogs of high potency and sustained action that, when administered in combination with exendin-4 or fibroblast growth factor 21 (FGF21), restores leptin responsiveness in DIO mice after an initial body weight loss of 30%. Using either combination, body weight loss was enhanced compared with either exendin-4 or FGF21 monotherapy, and leptin alone was sufficient to maintain the reduced body weight. In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. Accordingly, we find that a hypothalamic counter-regulatory response to weight loss, assessed using changes in hypothalamic agouti related peptide (AgRP) levels, is triggered by caloric restriction, but blunted by treatment with exendin-4. We conclude that leptin re-sensitization requires pharmacotherapy but does not appear to be restricted to a unique signaling pathway. Our findings provide preclinical evidence that high activity, long-acting leptin analogs are additively efficacious when used in combination with other weight-lowering agents. AU - Müller, T.D. AU - Sullivan, L.M.* AU - Habegger, K.* AU - Yi, C.-X.* AU - Kabra, D.* AU - Grant, E.* AU - Ottaway, N.* AU - Krishna, R.* AU - Holland, J.* AU - Hembree, J.* AU - Perez-Tilve, D.* AU - Pfluger, P.T. AU - DeGuzman, M.J.* AU - Siladi, M.E.* AU - Kraynov, V.S.* AU - Axelrod, D.W.* AU - DiMarchi, R.* AU - Pinkstaff, J.K.* AU - Tschöp, M.H. C1 - 7527 C2 - 29795 SP - 383-393 TI - Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. JO - J. Pept. Sci. VL - 18 IS - 6 PB - Wiley-Blackwell PY - 2012 SN - 1075-2617 ER - TY - JOUR AU - Deluca, D. AU - Woehlke, G.* AU - Moroder, L.* C1 - 22240 C2 - 20979 SP - 203-211 TI - Synthesis and Conformational Characterization of Peptides Related to the Neck Domain of a Fungal Kinesin. JO - J. Pept. Sci. VL - 9 PY - 2003 SN - 1075-2617 ER - TY - JOUR AU - Deluca, D. AU - Woehlke, G.* AU - Moroder, L.* C1 - 22276 C2 - 21049 SP - 203-211 TI - Synthesis and Conformational Characterization of Peptides Related to the Neck Domain of a Fungal Kinesin. JO - J. Pept. Sci. VL - 9 PY - 2003 SN - 1075-2617 ER -