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The demand for novel medications is escalating due to the diminishing efficacy of long-standing antibiotics. Chemists and pharmaceutical researchers are vigorously pursuing innovative compounds, particularly those with cell membrane-penetrating capabilities, as these are the only ones that can be administered orally in tablet or syrup form. Such active ingredients are able to traverse the intestinal barrier in the small intestine and swiftly enter the bloodstream to target the affected regions of the body. In contrast, for active ingredients that are unable to penetrate the cell membrane, healthcare providers have no alternative but to administer them via direct injection into the bloodstream.
Large molecules with potential
Researchers are actively investigating the molecular characteristics that enable substances to penetrate cell membranes, particularly cyclic peptides, which hold great promise. Scientists at ETH Zurich have recently unraveled further insights into the mechanism behind this process, shedding light on the properties that molecules must possess. "Enhancing our understanding of this mechanism and the required molecular properties can greatly accelerate and optimize the development of new drugs," explains Sereina Riniker, a professor at the Department of Chemistry and Applied Biosciences, who spearheaded the study. The findings have been published in the esteemed Journal of Medicinal Chemistry, contributing to the growing body of knowledge in this field.
Cyclic peptides, characterized by their ring-shaped structure, are a distinct class of molecules that surpass the size of typical small molecules commonly found in modern drugs. In certain applications, conventional small molecules are reaching their limitations, prompting chemists and pharmaceutical scientists to explore the potential of larger molecules such as cyclic peptides. This class of substances encompasses a plethora of biologically active natural compounds, including cyclosporine, a renowned immunosuppressant utilized in organ transplant patients for decades, as well as various antibiotics. The exploration of cyclic peptides as a viable option in drug development is gaining momentum in the field of pharmaceutical research.
Possible only with computer modelling
Through the utilization of cutting-edge computer modeling techniques and formidable supercomputer capabilities, Riniker and her team have successfully unraveled the intricate process by which cyclic peptides, akin to cyclosporine, traverse cell membranes. "Modeling is indispensable in providing us with detailed, high-resolution insights, as direct experimental observations of individual molecules crossing a membrane are not currently feasible," Riniker elucidates. This groundbreaking approach enables researchers to gain unprecedented understanding of the mechanisms underlying membrane penetration, paving the way for innovative drug development strategies and furthering the frontier of scientific knowledge in this field.
Gaining insight into the mechanism of cyclic peptides requires a comprehensive understanding of their unique structural composition. These molecules are characterized by a central ring structure that is adorned with side chains. Remarkably, cyclic peptides possess flexibility and can dynamically alter their conformation to adapt to their surroundings. This inherent adaptability allows cyclic peptides to effectively interact with cellular membranes and navigate through complex environments, making them intriguing candidates for drug development. Understanding the structural dynamics of cyclic peptides is crucial for elucidating their membrane penetration mechanism and harnessing their therapeutic potential.
Dance through the cell membrane
Riniker's pioneering simulations have unveiled a detailed portrayal of how cyclic peptides permeate cellular membranes. The process begins with the molecule anchoring itself to the surface of the membrane, followed by perpendicular penetration. As it traverses the membrane, the cyclic peptide undergoes a remarkable three-dimensional conformational change, rotating once around its longitudinal axis before emerging on the other side of the membrane. This dynamic behavior enables the cyclic peptide to efficiently navigate through the lipid bilayer and exit the membrane, shedding light on the intricate mechanism of membrane penetration at a molecular level. Such groundbreaking insights hold immense promise in advancing our understanding of cyclic peptide-mediated cellular interactions and their potential applications in drug development.
The conformational changes exhibited by cyclic peptides during membrane penetration are closely linked to the distinct environments they encounter along their journey. The human body, comprising mostly water, houses a plethora of biochemical molecules that exist in aqueous solutions within and outside of cells. In stark contrast, cell membranes are primarily composed of hydrophobic fatty acids, resulting in water-repellent conditions within the lipid bilayer. To successfully traverse this hydrophobic barrier, cyclic peptides adeptly alter their three-dimensional shape to momentarily optimize their hydrophobicity, enabling them to cross the membrane. Riniker elaborates, "The cyclic peptide transiently adopts a conformation that is as hydrophobic as possible, facilitating its passage through the membrane." This profound understanding of the interplay between cyclic peptides and their hydrophobic environment sheds light on the fascinating intricacies of membrane penetration at a molecular level and has significant implications for the development of novel drug delivery strategies.
Changing molecular side chains
The current study entailed an in-depth exploration of eight distinct cyclic peptides by the research team. These cyclic peptides were selected as model peptides without any medicinal properties, and were originally developed by scientists at the renowned pharmaceutical company Novartis for fundamental research purposes. As a result, Riniker collaborated closely with researchers from Novartis for this study, leveraging their expertise to advance our understanding of cyclic peptides and their membrane penetration mechanism. This interdisciplinary collaboration has shed light on the fascinating world of cyclic peptides and their potential implications for drug development, illustrating the significance of partnerships between academia and industry in advancing scientific knowledge and innovation.
The latest insights gained from this study have significant implications for identifying cyclic peptides as potential drug candidates. However, Riniker highlights a crucial trade-off that researchers must consider. While certain side chains may create favorable conditions for cyclic peptides to anchor to the membrane surface, they may also hinder the peptides' ability to cross the membrane. This newfound understanding empowers researchers to strategically select and position side chains on the cyclic peptide molecule to optimize its membrane penetration capabilities. This proactive approach can expedite the drug discovery and development process by ensuring that researchers focus on potential active ingredients that are more likely to be viable for oral administration in the form of tablets. By leveraging this knowledge from the outset, researchers can streamline the drug development pipeline and increase the chances of success in identifying effective cyclic peptide-based therapeutics.
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