Current Protein and Peptide Science - Volume 19, Issue 6, 2018

With the rapid increase of multiple drug-resistant bacteria, silver nanoparticles (AgNPs) with broad-spectrum antibacterial activities have been widely applied in the treatment of bacterial infection. Meanwhile, AgNPs also have anticancer activities against different cell lines. The toxic effects of AgNPs depend on concentration, size, shape, coated materials and surrounding environments. In order to better understand the antibacterial and antitumor effects of AgNPs, various investigations have been carried out to uncover the molecular mechanism of action. This review summarizes the recent studies on the action mechanisms of AgNPs related to their antibacterial activities including collapsing cell walls, inducing reactive oxygen species, inhibiting aerobic respiration and damaging DNA and their antitumor effects including impairing mitochondria, blocking cell cycle, and activating apoptosis. In these investigations, the systematic approaches have not been extensively applied. Increasingly matured omics techniques including genomics, transcriptomic, translatomics and proteomics should be more widely explored to provide the comprehensive views of the cytotoxic effects of AgNPs to bacteria and tumor cells and thus globally illustrate the molecular mechanisms of the cytotoxicity, promoting the better medical application of AgNPs in the future.

Identifying the interactions between drugs and target proteins is a key step in drug discovery. This not only aids to understand the disease mechanism, but also helps to identify unexpected therapeutic activity or adverse side effects of drugs. Hence, drug-target interaction prediction becomes an essential tool in the field of drug repurposing. The availability of heterogeneous biological data on known drug-target interactions enabled many researchers to develop various computational methods to decipher unknown drug-target interactions. This review provides an overview on these computational methods for predicting drug-target interactions along with available webservers and databases for drug-target interactions. Further, the applicability of drug-target interactions in various diseases for identifying lead compounds has been outlined.

Drug discovery and development is not only a time-consuming and labor-intensive process but also full of risk. Identifying targets of small molecules helps evaluate safety of drugs and find new therapeutic applications. The biotechnology measures a wide variety of properties related to drug and targets from different perspectives, thus generating a large body of data. This undoubtedly provides a solid foundation to explore relationships between drugs and targets. A large number of computational techniques have recently been developed for drug target prediction. In this paper, we summarize these computational methods and classify them into structure-based, molecular activity-based, side-effectbased and multi-omics-based predictions according to the used data for inference. The multi-omicsbased methods are further grouped into two types: classifier-based and network-based predictions. Furthermore#140; the advantages and limitations of each type of methods are discussed. Finally, we point out the future directions of computational predictions for drug targets.

Hemoglobin (Hb) is the prototypical example of a cooperative protein. Cooperativity of Hb is largely accounted for by the oxygen-linked allosteric interconversion between the T and R states/structures. Allostery is such a powerful explanation of Hb cooperativity that the possibility of cooperative events occurring within each allosteric conformation, in the absence of any quaternary structural change has usually been overlooked, and actually experiments specifically aimed at detecting nonallosteric cooperativity have usually failed to do so. However there are strong, but often neglected, theoretical reasons pointing to the presence of nonallosteric cooperativity under common experimental conditions, that have recently raised new interest and have been thoroughly re-investigated. Non-allosteric cooperativity within T state Hb has often been invoked to describe puzzling experimental data, either as an intrinsic property of the macromolecule or as a consequence of the binding of non-heme ligands. Few convincing pieces of evidence exist for the former hypothesis, whereas very strong proofs are available for effector-induced non-allosteric cooperativity in hemoglobin. Moreover, non-allosteric cooperativity in ^THb may explain some hitherto puzzling findings, e.g. the bi-exponential O2 release from ^THb observed by Q.H. Gibson in oxygen pulse experiments, the invariance of L4 found by K. Imai, the cooperative ligand binding by crystals of T state Hb Rotschild, and, possibly, the cooperativity observed in at least some mixed metal hybrid Hbs.

The vascular endothelial growth factor (VEGF) is a homodimeric disulfide bound glycoprotein that promotes endothelial growth, accompanied by higher vascular permeability, and therefore represents an important factor for angiogenesis and vascularization. In addition, VEGF also has a neurotrophic and neuroprotective impact on glial and neuronal cells within the CNS and PNS. Recently, we have shown that VEGF increases somato- and dendritogenesis in neonatal, but not in mature CNS neurons [1], and leads to axonal growth cone guidance during embryonic development of the PNS [2, 3]. We assume that microRNAs are involved in the neuronal plasticity by altering expression patterns of corresponding VEGF receptors [4]. Therefore, this review focuses on microRNAs and their impact on the regulation of neuronal development at the posttranscriptional level within the CNS and PNS. Besides this, recent data about the regenerative impact of VEGF in the CNS and PNS are discussed, with a close look at the expression of VEGF and its corresponding miRNAs in these neuronal structures.

Alpha synuclein (α-syn) belongs to a class of proteins which are commonly considered to play a detrimental role in neuronal survival. This assumption is based on the occurrence of a severe neuronal degeneration in patients carrying a multiplication of the α-syn gene (SNCA) and in a variety of experimental models, where overexpression of α-syn leads to cell death and neurological impairment. In these conditions, a higher amount of normally structured α-syn produces a damage, which is even worse compared with that produced by α-syn owning an abnormal structure (as occurring following point gene mutations). In line with this, knocking out the expression of α-syn is reported to protect from specific neurotoxins such as 1-methyl, 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). In the present review we briefly discuss these well-known detrimental effects but we focus on findings showing that, in specific conditions α-syn is beneficial for cell survival. This occurs during methamphetamine intoxication which is counteracted by endogenous α-syn. Similarly, the dysfunction of the chaperone cysteine-string protein- alpha leads to cell pathology which is counteracted by over-expressing α-syn. In line with this, an increased expression of α-syn protects against oxidative damage produced by dopamine. Remarkably, when the lack of α-syn is combined with a depletion of β- and γ- synucleins, alterations in brain structure and function occur. This review tries to balance the evidence showing a beneficial effect with the bulk of data reporting a detrimental effect of endogenous α-syn. The specific role of α-syn as a chaperone protein is discussed to explain such a dual effect.

Clusterin is a multifunctional glycoprotein whose role in cells has generated a great controversy in recent years. Since its discovery, numerous studies have linked clusterin expression deregulation with various physio-pathological processes such as cancer or Alzheimer's disease. Although the results of such investigations have sometimes been contradictory, mainly due to the dichotomous role of clusterin isoforms, it has been demonstrated that this protein is involved in diverse cellular processes, including apoptosis, cell cycle regulation, DNA repair or the acquisition of cell resistance against multiple conventional therapies. These results, together with the breakthrough of gene therapies, have motivated a great effort to elucidate the importance of clusterin as a potential therapeutic target. However, the understanding of a single gene, with multiple RNA transcripts and several protein isoforms has turned out to be a complex task. In this review, we summarize the studies published to date on factors that can affect clusterin expression and evaluate if a better understanding of this complex gene/protein would be useful to develop new treatment strategies for cancer and other pathologies.

Arginine-rich cell penetrating peptides (CPPs) are very promising drug carriers to deliver membrane-impermeable pharmaceuticals, such as siRNA, bioactive peptides and proteins. CPPs directly penetrate into cells across cell membranes via a spontaneous energy-independent process, in which CPPs appear to interact with acidic lipids in the outer leaflet of the cell membrane. However, acidic lipids represent only 10 to 20% of the total membrane lipid content and in mammalian cell membranes they are predominantly located in the inner leaflet. Alternatively, CPPs favorably bind in a charge density- dependent manner to negatively charged, sulfated glycosaminoglycans (GAGs), such as heparan sulfate and chondroitin sulfate, which are abundant on the cell surface and are involved in many biological functions. We have recently demonstrated that the interaction of CPPs with sulfated GAGs plays a critical role in their direct cell membrane penetration: the favorable enthalpy contribution drives the high-affinity binding of arginine-rich CPPs to sulfated GAGs, initiating an efficient cell membrane penetration. The favorable enthalpy gain is presumably mainly derived from a unique property of the guanidino group of arginine residues forming multidentate hydrogen bonding with sulfate and carboxylate groups in GAGs. Such interactions can be accompanied with charge neutralization of arginine-rich CPPs, promoting their partition into cell membranes. This review summarizes the current understanding of the physicochemical mechanism for lipid membrane penetration of CPPs, and discusses the role of the GAG interactions on the cell membrane penetration of CPPs.