Peptide modulators of alpha‐glucosidase

Aims/Introduction

Acute glucose fluctuations during the postprandial period pose great risk for cardiovascular complications and thus represent an important therapeutic approach in type 2 diabetes. In the present study, screening of peptide libraries was used to select peptides with an affinity towards mammalian intestinal alpha-glucosidase as potential leads in antidiabetic agent development.

Materials and Methods

Three phage-displayed peptide libraries were used in independent selections with different elution strategies to isolate target-binding peptides. Selected peptides displayed on phage were tested to compete for an enzyme-binding site with known competitive inhibitors, acarbose and voglibose. The four best performing peptides were synthesized. Their binding to the mammalian alpha-glucosidase and their effect on enzyme activity were evaluated.

Results

Two linear and two cyclic heptapeptides with high affinity towards intestinal alpha-glucosidase were selected. Phage-displayed as well as synthetic peptides bind into or to the vicinity of the active site on the enzyme. Both cyclic peptides inhibited enzyme activity, whereas both linear peptides increased enzyme activity.

Conclusions

Although natural substrates of glycosidase are polysaccharides, in the present study we successfully isolated novel peptide modulators of alpha-glucosidase. Modulatory activity of selected peptides could be further optimized through peptidomimetic design. They represent promising leads for development of efficient alpha-glucosidase inhibitors.     

A Sentinel Serological Study in Selected Zoo Animals to Assess Early Detection of West Nile and Usutu Virus Circulation in Slovenia

Monitoring infectious diseases is a crucial part of preventive veterinary medicine in zoological collections. This zoo environment contains a great variety of animal species that are in contact with wildlife species as a potential source of infectious diseases. Wild birds may be a source of West Nile virus (WNV) and Usutu (USUV) virus, which are both emerging pathogens of rising concern. The aim of this study was to use zoo animals as sentinels for the early detection of WNV and USUV in Slovenia. In total, 501 sera from 261 animals of 84 animal species (including birds, rodents, lagomorphs, carnivores, ungulates, reptiles, equids, and primates) collected for 17 years (2002–2018) were tested for antibodies to WNV and USUV. Antibodies to WNV were detected by indirect immunofluorescence tests in 16 (6.1%) of 261 animals representing 10 species, which were sampled prior to the first active cases of WNV described in 2018 in Slovenia in humans, a horse, and a hooded crow (Corvus cornix). Antibodies to USUV were detected in 14 out of 261 animals tested (5.4%) that were positive prior to the first positive cases of USUV infection in common blackbirds (Turdus merula) in Slovenia. The study illustrates the value of zoological collections as a predictor of future emerging diseases.     

Expression of cyclooxygenase-2, glucose transporter-1 and angiogenesis in gallbladder carcinomas and their impact on prognosis

Objective. To investigate the angiogenic and prognostic role of cyclooxygenase-2 (COX-2) in gallbladder carcinomas. We assume COX-2 overexpression, neoangiogenesis and glucose transporter-1 (GLUT-1) to be involved in disease progression. Material andmethods. The carcinoma tissues of 56 patients with gallbladder carcinomas were studied immunohistochemically for the expression of COX-2, GLUT-1 and micro-vessel density. The results were correlated with clinico-pathological features and survival/prognosis. Results. The overexpression of COX-2 in gallbladder carcinomas was significantly associated with increased angiogenesis and GLUT-1 expression. Neither angiogenesis nor the grade of the tumour correlate significantly with poor survival. Age, gender and a strong GLUT-1 expression were significant factors of adverse prognosis. Conclusions. Next to age and gender of patients, hypoxia of gallbladder tumours is a factor influencing survival. Among hypoxic factors, GLUT-1 expression is an important (significant) denominator of poor prognosis in gallbladder carcinomas, but not COX-2 nor angiogenesis.     

Multiple infections after commercial renal transplantation in India.

Sir, The increased demand for transplantable kidneys has not metwith a corresponding increase in the supply of these organs.Many patients travel to other, mostly developing countries,in search of commercial transplantation. In order to performthe procedure rapidly, standards of transplantation are compromised[1]. Besides the clinical issues, ethical problems are alsoof equal concern. We report the case of a 56-year-old Slovenian male who underwentrenal transplantation for     

4-Substituted trinems as broad spectrum beta-lactamase inhibitors: structure-based design, synthesis, and biological activity

A wide variety of pathogens have acquired antimicrobial resistance as an inevitable evolutionary response to the extensive use of antibacterial agents. In particular, one of the most widely used antibiotic structural classes is the beta-lactams, in which the most common and the most efficient mechanism of bacterial resistance is the synthesis of beta-lactamases. Class C beta-lactamase enzymes are primarily cephalosporinases, mostly chromosomally encoded, and are inducible by exposure to some beta-lactam agents and resistant to inhibition by marketed beta-lactamase inhibitors. In an ongoing effort to alleviate this problem a series of novel 4-substituted trinems was designed and synthesized. Significant in vitro inhibitory activity was measured against the bacterial beta-lactamases of class C and additionally against class A. The lead compound LK-157 was shown to be a potent mechanism-based inactivator. Acylation of the active site Ser 64 of the class C enzyme beta-lactamase was observed in the solved crystal structures of two inhibitors complexes to AmpC enzyme from E. cloacae. Structure-activity relationships in the series reveal the importance of the trinem scaffold for inhibitory activity and the interesting potential of the series for further development.     

Should the patients colonized with extended-spectrum beta-lactamase-producing Gram-negative bacilli (E-GNB) coming to hospital from the community with pneumonia get anti-E-GNB active empirical treatment?

Extended-spectrum beta-lactamases are responsible for resistance of Gram-negative bacilli to several beta-lactam antibiotics, including those prescribed for treatment pneumonia. To evaluate the importance of colonization with E-GNB for the choice of empirical treatment we performed a retrospective case-control study including 156 patients, hospitalized for treatment of pneumonia from 2009 through 2013. Empirical treatment success and in-hospital survival were significantly lower in patients colonized with E-GNB compared to non-colonized (p = 0.002, p = 0.035). When comparing subgroups of colonized patients, treatment success was significantly lower in patients who were colonized with E-GNB resistant to empirical antibiotic (p = 0.010), but not in those colonized by E-GNB susceptible to empirically given antibiotic (p = 0.104). Difference in in-hospital mortality was insignificant in both subgroups (p = 0.056, p = 0.331). The results of study suggest that an anti-E-GNB active antibiotic should be used for empirical treatment of pneumonia in E-GNB colonized patients.