[Bhm Monster Lab.epub
Iberio Ralda
In Folktales of Mexico, compiled by Amrico Paredes (one of the founding fathers of Chicano studies in the U.S.), I read a story about a man who discovered that his wife was a monster. Any night the man was away, the wife stripped away her skin and flew through the air as a skeleton, terrorizing the people of the town and stealing infants to eat.
It is a fortuitous event that spawns The Imp: a baby's first laugh, intertwined with a last sigh from her grandfather. This rarest of magic creates a Monster Who Wasn't. Named Imp by the gargoyles who adopt him, he is a rare creature indeed, human looking but with monster qualities but he possesses something more - something the monsters desire. As he rapidly learns about the world around him, he encounters some special humans. The bond he feels to them leads him on a nail-biting adventure. But will they love him or blame him for the terrible thing that has happened? Author TC Shelley builds oodles of tension in her book as we fly from page to page desperate to know just what will happen to Samuel and his gargoyle friend. The imaginative world of monsters, imps, pixies, gargoyles and many more are brought to life with graphic descriptions and terrifying action as she allows us mere humans a glimpse into the magical world that is swirling around us. Recommended for ages 7+. Curriculum links to descriptive writing, creating tension, new beginnings, friendships, hope, love, loyalty, bullying and resilience. 288 pages / Ages 7-10 years / Reviewed by Donna Burkert, teacher
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Peptide drug development has made great progress in the last decade thanks to new production, modification, and analytic technologies. Peptides have been produced and modified using both chemical and biological methods, together with novel design and delivery strategies, which have helped to overcome the inherent drawbacks of peptides and have allowed the continued advancement of this field. A wide variety of natural and modified peptides have been obtained and studied, covering multiple therapeutic areas. This review summarizes the efforts and achievements in peptide drug discovery, production, and modification, and their current applications. We also discuss the value and challenges associated with future developments in therapeutic peptides.
Therapeutic peptides are a unique class of pharmaceutical agents composed of a series of well-ordered amino acids, usually with molecular weights of 500-5000 Da1. Research into therapeutic peptides started with fundamental studies of natural human hormones, including insulin, oxytocin, vasopressin, and gonadotropin-releasing hormone (GnRH), and their specific physiological activities in the human body2. Since the synthesis of the first therapeutic peptide, insulin, in 1921, remarkable achievements have been made resulting in the approval of more than 80 peptide drugs worldwide. The development of peptide drugs has thus become one of the hottest topics in pharmaceutical research.
The first half of the 20th century witnessed the discovery of several life-saving bioactive peptides, such as insulin and adrenocorticotrophic hormone, which were initially studied and isolated from natural sources. The discovery and development of insulin, a peptide with 51 amino acids, has been considered as one of the monumental scientific achievements in drug discovery. It was first isolated by Frederick Banting in 1921 and further developed by Frederick and Charles Best3,4, and was already available for patients with diabetes mellitus just a year after its first isolation. In 1923, insulin became the first commercial peptide drug and has since benefited thousands of diabetes patients to date. However, the production of human insulin during the 20th century could not keep up with the high market demand, and animal-derived insulins, such as bovine and porcine insulin, dominated the insulin market for almost 90 years until they were replaced by recombinant insulin5,6.
More peptide hormones and their receptors with therapeutic potential were identified and characterized from the 1950s to the 1990s7. Meanwhile, the technologies used for protein purification and synthesis, structure elucidation, and sequencing made substantial progress, thus accelerating the development of peptide drugs, leading to nearly 40 peptide drugs being approved worldwide. Notably, synthetic peptides such as synthetic oxytocin8, synthetic vasopressin9, and recombinant human insulin10,11 began to be developed in addition to natural peptides.
Peptide drug development entered a new era with the advent of the 21st century, since when advances in structural biology, recombinant biologics, and new synthetic and analytic technologies have significantly accelerated the process. A sophisticated system of peptide drug development has been established, including peptide drug discovery, drug design, peptide synthesis, structural modification, and activity evaluation. A total of 33 non-insulin peptide drugs have been approved worldwide since 2000 (Table 1). In addition, these peptide drugs are no longer simply hormone mimics or composed simply of natural amino acids. For example, enfuvirtide is a 36-amino acid biomimetic peptide mimicking human immunodeficiency virus (HIV) proteins used in combination therapy for the treatment of HIV-112,13; ziconotide14,15 is a neurotoxic peptide derived from the cone snail Conus magus, which was approved in 2004 and is used to manage severe chronic pain; teduglutide is a glucagon-like peptide 2 (GLP-2) analogue used to treat short bowel syndrome16,17, and is manufactured using a strain of Escherichia coli modified by recombinant DNA technology; and liraglutide is a chemically synthesized analogue of human glucagon-like peptide 1(GLP-1)18,19, made by attaching a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on lysine residue (position 26 in the sequence), which acts as a GLP-1 receptor agonist to manage type 2 diabetes mellitus (T2DM). All these peptide drugs have been used in a wide range of therapeutic areas, such as urology, respiratory, pain, oncology, metabolic, cardiovascular, and antimicrobial applications20,21,22,23,24. To date, more than 170 peptides are in active clinical development (Table 2), with many more in preclinical studies1,7.
In this article, we review the historical development of peptide drugs and current advances in peptide drug discovery. We focus on the pharmaceutical characteristics of therapeutic peptides and highlight new technologies that have improved the design, synthesis, modification, and evaluation of peptide drugs, and provide new perspectives in the applications of peptide drugs. We also refer readers to several recent reviews for further reading1,7,28.
Therapeutic peptides commonly act as hormones, growth factors, neurotransmitters, ion channel ligands, or anti-infective agents. They bind to cell surface receptors and trigger intracellular effects with high affinity and specificity, with a similar mode of action to biologics, including therapeutic proteins and antibodies. However, compared with biologics, therapeutic peptides show less immunogenicity and have lower production costs29,30,31,32.
As natural amino acid-based therapeutics, therapeutic peptides have two intrinsic drawbacks (Fig. 2): membrane impermeability and poor in vivo stability, which represent major stumbling blocks for peptide drug development2,29.
Peptides have weak membrane permeability. The membrane permeability of peptide drugs depends on multiple factors, including peptide length and amino acid composition. Peptides are generally unable to cross the cell membrane to target intracellular targets, thus limiting their applications in drug development. Lau et al. reported in 2018 that >90% of peptides in active clinical development targeted extracellular targets, including G-protein coupled receptors (GPCRs), gonadotropin-releasing hormone (GnRH) receptor, Glucagon-like peptide 1 (GLP-1) receptor7.
Peptides have poor in vivo stability. Natural peptides consist of chains of amino acids joined by amide bonds, but lack the stability conferred by secondary or tertiary structures. The amide bonds can be easily hydrolyzed or destroyed by enzymes in vivo, upon exposure to the environment, without any protection. These inherent chemical properties make the peptides chemically and physically unstable, with a short half-life and fast elimination in vivo47.
The history of peptide drug discovery started by exploiting natural hormones and peptides with well-studied physiological functions for treating diseases caused by hormone deficiencies, such as a lack of insulin required to regulate blood glucose levels in patients with T1DM or T2DM. Diabetes is treated either by insulin injection or by stimulating insulin secretion-related targets such as GLP-1 receptor, to produce insulin48. Searching for natural peptides and hormones or replace them by animal homologues, such as insulin, GLP-1, somatostatin, GnRH, 8-Arg-Vasopressin, and oxytocin, were the initial strategies used for peptide drug discovery and development (Fig. 3). However, the drawbacks associated with these natural peptides aroused interest in optimizing their natural sequences, leading to a series of natural hormone-mimetic peptide drugs.
GLP-1 derived peptide drugs (Fig. 4a): GLP-1 is a 37-amino acid peptide that regulates insulin production and secretion49, with a very short half-life in vivo. Extensive efforts have been made to modify its sequence to enhance the stability of this hormone, while maintaining its potency and pharmacological effect50,51, leading to the development of the three top-selling anti-T2DM peptide drugs: Trulicity (dulaglutide), Victoza (liraglutide), and Ozempic (semaglutide).
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