Current Medicinal Chemistry - Volume 23, Issue 41, 2016

Virtually every living organism produces gene-encoded antimicrobial peptides (AMPs) that provide an immediate defence against pathogen invasion. Many AMPs have been isolated and used as antibiotics that are effective against multidrug-resistant bacteria. Although encouraging, AMPs have such poor drug-like properties that their application for clinical use is restricted. In turn, this has diverted research to the development of synthetic molecules that retain the therapeutic efficacy of AMPs but are endowed with greater biological stability and safety profiles. Most of the synthetic molecules, either based on a peptidic or non-peptidic scaffold, have been designed to mimic the amphiphilic properties of native AMPs, which are widely believed to be the key determinant of their antibacterial activity. In this review, the structural, chemical and biophysical features that govern the biological activities of various synthetic designs are discussed extensively. Recent innovative approaches from the literature that exhibit novel concepts towards the development of new synthetic antibacterial agents, including the engineered delivery platform incorporated with AMP mimetics, are also emphasised.

Multidrug resistance (MDR) describes the resistance of tumor cells to chemotherapy and has been ascribed to the overexpression of drug efflux pumps. Molecular imaging of drug efflux pumps is helpful to identify the patients who may be resistant to the chemotherapy and thus will avoid the unnecessary treatment and increase the therapeutic effectiveness. Imaging probes targeting drug efflux pumps can non-invasively evaluate the Pgp function and play an important role in identification of MDR, prediction of response, and monitoring MDR modulation. On the other hand, new anticancer agents based on molecular targets such as epidermal growth factor receptor (EGFR) and angiogenic factor receptor may potentially be combined with chemotherapeutic drugs to overcome the MDR. Imaging of molecular targets visualize treatment response of patients at molecular level vividly and help to select right patients for certain targeted anticancer therapy. Among all the imaging modalities, nuclear imaging including positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging has the greatest promise for rapid translation to the clinic and can realize quantitative visualization of biochemical processes in vivo. In this review, we will summarize the nuclear imaging probes utilized for predicting and evaluating the early anticancer therapy response. 99mTc labeled agents and PET based radiopharmaceuticals like 18F-Paclitaxel, 11C-Verapamil for drug efflux pumps imaging will be discussed here. Moreover, molecular imaging probes used for targeted therapy response evaluation like 18F-Tamoxifen, 89Zr-Trastuzumab will also be introduced in this review.

Background: Resveratrol may possess life-prolonging and health-benefitting properties, some of which may resemble the effect of caloric restriction (CR). CR appears to prolong the lifespan of model organisms in some studies and may benefit human health. However, for humans, restricting food intake for an extended period of time seems impracticable and substances imitating the beneficial effects of CR without having to reduce food intake could improve health in an aging and overweight population. Methods: We have reviewed the literature studying the influence of resveratrol on the lifespan of model organisms including yeast, flies, worms, and rodents. We summarize the in vivo findings, describe modulations of molecular targets and gene expression observed in vivo and in vitro, and discuss how these changes may contribute to lifespan extension. Data from clinical studies are summarized to provide an insight about the potential of resveratrol supplementation in humans. Results: Resveratrol supplementation has been shown to prolong lifespan in approximately 60% of the studies conducted in model organisms. However, current literature is contradictory, indicating that the lifespan effects of resveratrol vary strongly depending on the model organism. While worms and killifish seemed very responsive to resveratrol, resveratrol failed to affect lifespan in the majority of the studies conducted in flies and mice. Furthermore, factors such as dose, gender, genetic background and diet composition may contribute to the high variance in the observed effects. Conclusion: It remains inconclusive whether resveratrol is indeed a CR mimetic and possesses life-prolonging properties. The limited bioavailability of resveratrol may further impede its potential effects.

Targeting double-stranded DNA (dsDNA) with high affinity and specificity has become a hot topic in biochemistry and molecular biology research. Gene diagnosis and therapy, DNA manipulation, and gene expression regulation could be achieved based on certain recognition principles through specific interactions between dsDNA and natural nucleotides or synthesized ligands. Some ligands (e.g., peptide nucleic acids (PNAs), triple helix-forming oligonucleotides (TFOs), oligopolyamides, and zinc-finger peptides) show sufficient affinity and specificity for targeting dsDNA sequences. PNA can simply synthesize and recognize dsDNA without sequence limitation under physiological conditions. This paper provides a review on the recognition mechanisms, influencing factors, and applications of the four recognition modes of PNA targeting dsDNA. These modes include triplex invasion, triplex binding, duplex invasion, and double duplex invasion. This paper also discusses the challenges to be addressed by future research to fully explore the potential of PNA probe design for specific dsDNA recognition.

IRE1 signaling is the most evolutionarily conserved branch in the UPR. IRE1 is an ER stress sensor and provides a structure-based platform for the unfolded proteins docking, which causes the luminal domain conformational change and oligomerization. This selfassociation of IRE1 facilitates the phosphorylation of activation loop, which unlocks the autoinhibition in the kinase domain. The activating mechanistic cascade is thus initiated to induce DFG-in conformational change and movement of αC-helix to the active site. Structurally, RNase activity is coupled to autophosphorylation and activation of kinase domain. Consequently, the activation of RNase domain in human IRE1 indicates the conformational rearrangement switching the structural arranging pattern from face-to-face to back-to-back. IRE1 is still under investigation for target-specific drug development. Two types of ATP-competitive inhibitors of IRE1 kinase are introduced to modify RNase activity, regulating the UPR in response to ER stress. However, once the high activation of RNase surpasses the threshold, its biological roles will switch from adaption to destruction. This might explain for the dual functions of IRE1 in pro-survival and pro-apoptosis. Structural and mechanistic studies of IRE1 highlight the challenge of controlling the UPR in diseases.