Efforts to fight HIV infection have included the development of drugs that disrupt the integration of proviral DNA into the host genome. Researchers based at Monash Institute of Pharmaceutical Sciences, Australia, have developed cyclic hexapeptides that disrupt the interaction between the viral integrase and a key protein involved in viral import, lens epithelium-derived growth factor (LEDGF/p75). The peptides closely mimicked the structure of the LEDGF binding domain but their low affinities indicate that more interactions must be included in order to achieve the potency needed for an effective drug.

New approaches are needed in the fight against antibiotic resistance. One is the use of short antimicrobial peptides that selectively disrupt the membranes of bacteria. A collaboration between the Hospital for Sick Children, Toronto, and the University of Toronto has led to new insights into how antimicrobial peptide activity can be modulated using stapling and substitution of residues. This is a promising approach in the development of new peptide therapeutics.
Antimicrobial peptides are generally short (6–50 aa), with one of the largest categories being cationic antimicrobial peptides (CAPs). These peptides are rich in positively charged amino acids such as Lys and Arg and also have a hydrophobic region rich in large aromatics. The CAPs adopt an α-helix that folds to present the positively charged face to the aqueous medium while the hydrophobic face specifically targets the abundant negatively charged lipid head groups in bacterial membranes and weakens or disrupts the membrane to kill the bacterium. In this review article, the authors report the application of a hydrocarbon staple to a rationally-designed cationic antimicrobial peptide (CAP) that acquires increased membrane targeting and interaction vs. its linear counterpart.

Ovarian cancer (OVC) patients often acquire resistance to cytotoxic drugs such as cisplatin, doxorubicin, and paclitaxel within a year, leading to a disease recurrence rate of up to 80%. Hyun Hee Lee and colleagues at Weill Cornell Medicine, New York, USA have used a peptide to target the G-protein coupled receptor 4 (CXCR4) that plays a significant role in promoting tumorigenesis and drug resistance. The research team has shown that targeting a CXCR4^High cancer stem cell population with a selective peptide resulted in a synergistic cytotoxic effect when combined with chemotherapy agents such as doxorubicin and cisplatin. This is a promising approach in fighting drug resistance and improving treatment outcomes.

The incidence of esophageal adenocarcinoma (EAC) is rapidly increasing, with 450,000 new cases diagnosed and 400,000 deaths reported annually worldwide. Early detection is complicated by difficulty in detecting the flat premalignant lesions. However, the overexpression of cell surface fibroblast growth factor receptor 2 (FGFR2) is an early event in disease progression. A team comprising researchers based at the University of Michigan, USA and The Fourth Military Medical University, China, have identified a peptide that binds with high specificity to the extracellular domain of FGFR2, making this peptide a promising clinical imaging agent for early detection of esophageal adenocarcinoma.

The uncertainties of the long-term stability and effects of artificial materials in the human body have stimulated research into more natural materials for many biomedical applications. This search has lead to the discovery of peptide hydrogels, a highly promising family of constructs that are capable of self-assembly, typically into β-sheets, and can emulate the properties of natural materials such as collagen. Fine-tuning the mechanical properties of hydrogels to solve biomedical problems is, however, a real challenge. A team headed by researchers at the University of Auckland in New Zealand has come one step further with peptide hydrogels that are reversibly thermoresponsive. Their innovative hydrogels are based on multifunctional peptides that combine a hydrogel-forming β-sheet peptide segment, an enzyme substrate that enables biodegradation, and a RGD sequence to promote cell adhesion.

The list of scientific publications by users of our peptide synthesizers is growing steadily.This review article is based on a recent article in the European Journal of Medicinal Chemistry by Rahul Kumar and colleagues at All India Institute of Medical Sciences and School of Computational and Integrative Sciences, Jawaharlal Nehru University in New Delhi, India.

In this study, Rahul Kumar and his colleagues designed and synthesized a novel peptide SIRT1 activator. SIRT1 has been shown to have a protective role against Alzheimer's disease.The peptide, CWR, was tested for its effect on the activity of recombinant SIRT1 protein and also determining its cytotoxicity. CWR was found to be a potent allosteric activator of SIRT1 both by molecular docking and in vitro analysis, increased cell viability and no toxicity to human erythrocytes were also observed.

Anomalous protein aggregation has been pinpointed as a prime cause of a number of serious neurodegenerative diseases that include Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob. In the case of Alzheimer’s, protein aggregation starts with cleavage of an amyloid precursor protein (APP) by a secretase to form amyloid-β (Aβ), a family of peptides that form toxic fibrillar plaques, leading to progressive neuron degeneration. This insight has hastened the search for methods to prevent plaque formation. The cholesterol-rich membrane microdomains that promote secretase activity appear to be involved. Added to that, free cholesterol in the cytoplasm can promote the aggregation of Aβ peptides into fibrils, and cholesterol can interact directly with APP and Aβ amyloid fibrils. With this in mind, Elbassal and colleagues at Florida Atlantic University, USA, investigated how cholesterol and its derivatives could affect the formation of fibrils. They showed that the structural properties of the cholesterol-derivative vesicles, including surface charge and vesicle size, are critical in regulating their effect on Aβ40 aggregation kinetics.

The search for new drug classes has gone beyond the classically druggable genome, which appears to be limited to around 1,500 proteins. One route is the development of molecules that interfere with the Protein-Protein Interactions (PPIs) that are critical to all cellular processes, such as the regulation of cell growth, DNA replication, transcriptional activation, protein folding, and transmembrane signaling. One PPI-based drug target that involves a well-defined secondary structure is the interaction between the p53 tumor suppressor, the so-called “guardian of the genome” involved in programmed cell death, and MDM2, an important negative regulator of p53. This interaction involves a “hot spot triad” of three residues, Phe19, Trp23 and Leu26, on one face of the α-helical region of p53. Mimicking this region with a peptide became the focus of a collaborative effort between University of Gothenburg, Sweden and St. Jude Children’s Research Hospital in Tennessee, USA and resulted in key insights into the balanced peptide design required to achieve effective PPI inhibition (Danelius et al, 2016).

In the search for ways to handle soft materials at the nano-level, Polyelectrolyte Complexes (PECs) offer a lot of promise. They self-assemble and their enormous diversity of structure and chemical composition enable functionality to be fine-tuned. The biocompatibility and biodegradability of peptide polymer PECs means they are particularly useful in such as food additive encapsulation, micellar drug delivery, and scaffolding cell growth for tissue engineering. The physical properties of peptide polymer PECs can be modulated based on many factors. Naomi Pacalin, Lorraine Leon, and Matthew Tirrell at the University of Chicago, USA, have shown that changing the chirality of peptide polymer PECs alters the strength of polymer chain interactions, allowing chirality to be used to tailor polymers to have the precise properties needed for a particular application (Eur. Phys. J. Spec. Top., 2016, 225:1805).