Current Topics in Medicinal Chemistry - Volume 20, Issue 32, 2020

Cardiovascular diseases (CVDs) are the leading global cause of death, accounting for more than 17.6 million deaths per year in 2016, a number that is expected to grow to more than 23.6 million by 2030. While many technologies are currently under investigation to improve the therapeutic outcome of CVD complications, only a few medications have been approved. Therefore, new approaches to treat CVD are urgently required. Peptides regulate numerous physiological processes, mainly by binding to specific receptors and inducing a series of signals, neurotransmissions or the release of growth factors. Importantly, peptides have also been shown to play an important role in the circulatory system both in physiological and pathological conditions. Peptides, such as angiotensin II, endothelin, urotensin-II, urocortins, adrenomedullin and natriuretic peptides have been implicated in the control of vascular tone and blood pressure as well as in CVDs such as congestive heart failure, atherosclerosis, coronary artery disease, and pulmonary and systemic hypertension. Hence it is not surprising that peptides are becoming important therapeutic leads in CVDs. This article will review the current knowledge on peptides and their role in the circulatory system, focusing on the physiological roles of natriuretic peptides in the cardiovascular system and their implications in CVDs.

Cells are mainly dependent on glucose as their energy source. Multicellular organisms need to adequately control individual glucose uptake by the cells, and the insulin-glucagon endocrine system serves as the key glucose regulation mechanism. Insulin allows for effective glucose entry into the cells when blood glucose levels are high, and glucagon acts as its opponent, balancing low blood glucose levels. A lack of insulin will prevent glucose entry to the cells, resulting in glucose accumulation in the bloodstream. Diabetes is a disease which is characterized by elevated blood glucose levels. All diabetes types are characterized by an inefficient insulin signaling mechanism. This could be the result of insufficient insulin secretion, as in the case of type I diabetes and progressive incidents of type II diabetes or due to insufficient response to insulin (known as insulin resistance). We emphasize here, that Diabetes is actually a disease of starved tissues, unable to absorb glucose (and other nutrients), and not a disease of high glucose levels. Indeed, diabetic patients, prior to insulin discovery, suffered from glucose malabsorption. In this mini-review, we will define diabetes, discuss the current status of diabetes treatments, review the current knowledge of the different hormones that participate in glucose homeostasis and the employment of different modulators of these hormones. As this issue deals with peptide therapeutics, special attention will be given to synthetic peptide analogs, peptide agonists as well as antagonists.

The manipulation of an individual’s genetic information to treat a disease has revolutionized the biomedicine field. Despite the promise of gene therapy, this treatment can have long-term sideeffects. Efforts in the field and recent discoveries have already led to several improvements, including efficient gene delivery and transfer, as well as inpatient safety. Several studies to treat a wide range of pathologies-such as cancer or monogenic diseases- are currently being conducted. Here we provide a broad overview of methodologies available for gene therapy, placing a strong emphasis on treatments for central nervous system diseases. Finally, we give a perspective on current delivery strategies to treat such diseases, with a special focus on systems that use peptides as delivery vectors.

Peptide receptor radionuclide therapy (PRRT) is a highly effective anti-cancer treatment modality for patients with non-resectable, metastasized neuroendocrine tumors (NETs). During PRRT, specific receptors that are overexpressed on the cancer cells are targeted with a peptide labeled with a DNA-damaging radionuclide. Even though PRRT is a powerful treatment for metastasized NET patients, the majority still cannot be cured at this stage of the disease. Hence, many investigators focus on improving the therapeutic efficacy of this therapy. Improving PRRT can, for example, be achieved by using other radionuclides with different physical properties, by combining PRRT with radiosensitizing agents or by radiolabeling peptides with different characteristics. However, due to lack of extensive knowledge of radiobiological responses of cancer cells to PRRT, biological parameters that influence absorbed dose or that might even elicit insensitivity to therapy remain elusive and the context in which these improvements will be successful warrants further investigation. In this review, we will discuss the development of PRRT, its clinical merits in current treatment and future perspectives. We will highlight different radionuclides and their benefits and pitfalls, as well as different peptide-conjugates that hold these radionuclides. We will zoom in on the latest developments regarding combinatorial treatments and how investigators from different disciplines such as dosimetry and radiobiology are now joining forces to improve PRRT for NETs.

Antimicrobial peptides (AMPs) are a class of peptides found across a wide array of organisms that play key roles in host defense. AMPs induce selective death in target cells and orchestrate specific or nonspecific immune responses. Many AMPs exhibit native anticancer activity in addition to antibacterial activity, and others have been engineered as antineoplastic agents. We discuss the use of AMPs in the detection and treatment of cancer as well as mechanisms of AMP-induced cell death. We present key examples of cathelicidins and transferrins, which are major AMP families. Further, we discuss the critical roles of protein-protein interactions (PPIs) in cancer and how AMPs are well-suited to target PPIs based on their unique drug-like properties not exhibited by small molecules or antibodies. While peptides, including AMPs, can have limited stability and bioavailability, these issues can be overcome by peptide backbone modification or cyclization (e.g., stapling) and by the use of delivery systems such as cellpenetrating peptides (CPPs), respectively. We discuss approaches for optimizing drug properties of peptide and peptidomimetic leads (modified peptides), providing examples of promising techniques that may be applied to AMPs. These molecules represent an exciting resource as anticancer agents with unique therapeutic advantages that can target challenging mechanisms involving PPIs. Indeed, AMPs are suitable drug leads for further development of cancer therapeutics, and many studies to this end are underway.

Background: Antibiotic resistance is a global issue and new anti-microbials are required. Introduction: Anti-microbial peptides are important players of host innate immune systems that prevent infections. Due to their ability to eliminate drug-resistant pathogens, AMPs are promising candidates for developing the next generation of anti-microbials. Methods: The anti-microbial peptide database provides a useful tool for searching, predicting, and designing new AMPs. In the period from 2015-2019, ~500 new natural peptides have been registered. Results: This article highlights a selected set of new AMP members with interesting properties. Teixobactin is a cell wall inhibiting peptide antibiotic, while darobactin inhibits a chaperone and translocator for outer membrane proteins. Remarkably, cOB1, a sex pheromone from commensal enterococci, restricts the growth of multidrug-resistant Enterococcus faecalis in the gut at a picomolar concentration. A novel proline-rich AMP has been found in the plant Brassica napus. A shrimp peptide MjPen- II comprises three different sequence domains: serine-rich, proline-rich, and cysteine-rich regions. Surprisingly, an amphibian peptide urumin specifically inhibits H1 hemagglutinin-bearing influenza A virus. Defensins are abundant and typically consist of three pairs of intramolecular disulfide bonds. However, rat rattusin dimerizes via forming five pairs of intermolecular disulfide bonds. While human LL-37 can be induced by vitamin D, vitamin A induces the expression of resistin-like molecule alpha (RELMα) in mice. The isolation and characterization of an alternative human cathelicidin peptide, TLN-58, substantiates the concept of one gene multiple peptides. The involvement of a fly AMP nemuri in sleep induction may promote the research on the relationship between sleep and infection control. Conclusion: The functional roles of AMPs continue to grow and the general term “innate immune peptides” becomes useful. These discoveries widen our view on the anti-microbial peptides and may open new opportunities for developing novel peptide therapeutics for different applications.