Current Pharmaceutical Biotechnology - Volume 14, Issue 11, 2013

Tuberculosis (TB) is an infectious disease caused mainly by members of Mycobacterium tuberculosis complex. In 2012, the WHO estimated 8.7 million new cases and 1.4 million deaths caused by this disease. Under the Millennium Development Goals, the WHO aims to eradicate TB as a public health problem by 2050. However, reaching this goal will require the development and incorporation of new and more effective vaccines that can replace the current BCG vaccine. Much work is therefore ongoing in terms of the development of TB vaccines and more than 10 candidate vaccines are progressing well through the different development stages. The aim of this mini-review is to describe the characteristics of the most promising vaccines, and to give a brief description of some key elements relating to the current and future development of vaccines against TB.

Streptococcus pyogenes or Group A Streptococcus (GAS) is a major Gram-positive human pathogen that causes diverse human diseases with a high morbidity and mortality worldwide. The development of an effective GAS vaccine is hindered by the occurrence of many unique GAS serotypes, the complexity of the global epidemiology of GAS infections, and safety concerns over the cross-reactivity of some antigen-specific antibodies with human tissues and proteins. Although no licensed GAS vaccine is available, a number of candidate vaccines have been or are being evaluated in laboratory or in clinical trials. This minireview provides brief information on the progress and difficulty in the development of GAS vaccines.

Pseudomonas aeruginosa is one of the major pathogens responsible for a wide variety of severe nosocomial and community acquired infections. Numerous vaccine candidates and several monoclonal antibodies have been developed over the past 40 years but only a few have reached clinical trials and none of these vaccine candidates has obtained market authorization. The understanding of P. aeruginosa pathogenesis and its virulence factors is essential in the identification of immunogens that can be used for a P. aeruginosa vaccine. This review summarizes the present status of vaccine development for this important pathogen.

Although dental caries is a global problem in modern times, no vaccines are available for preventing these diseases. Among the bacterial pathogens that cause dental caries, including Streptococcus mutans, S. sobrinus, and Lactobacillus acidophilus, and Actinomyces viscosus, S. mutans is the most prominent and prevalent species. During the past, much effort has been focused on developing vaccines against S. mutans. Early attempts used fixed whole cells of S. mutans, but later it was found that serological cross-reactivity between heart tissue antigens and Streptococcus antigens occurs in patients resulting in rheumatic fever. Recently, with the aid of molecular biology, the genome sequences of S. mutans strains are available, which can greatly accelerate the development of subunit vaccines. Many desirable candidate subunit vaccines have been or are going to be evaluated in either experimental animal models or in human clinical trials. In this review article, we summarized the updated progress made in deciphering the mechanisms of disease development and the achievements of vaccine research against S. mutans.

Urinary tract infections (UTIs) are one of the most common infectious diseases of humans, with approximately 150 million cases estimated to occur globally every year. UTIs usually start as a bladder infection (cystitis), but can develop into acute kidney infection (pyelonephritis) and even infection of the bloodstream (urosepsis). The high frequency of UTIs in community and nosocomial settings places an enormous burden on healthcare systems worldwide. Multiple different pathogens cause UTI, with uropathogenic E. coli (UPEC) the most common etiological agent. UTIs caused by these pathogens are increasingly associated with antibiotic resistance, thus severely reducing treatment options and significantly increasing UTI-associated morbidity and mortality. In this review we present an overview of the recent advances in vaccine research targeted towards the prevention of UPEC-mediated UTI. In the context of multidrug resistance, we conclude that vaccination represents a viable approach for the prevention of chronic and recurrent UTI.

Acetaminophen is a common analgesic and antipyretic compound which, when administered in high doses, has been associated with significant morbidity and mortality, secondary to hepatic toxicity. Although this may be due to a direct interaction of reactive acetaminophen metabolites with hepatocyte proteins, recent studies have suggested that reactive species produced by neutrophils also contribute to the pathophysiological process. Researches on the chemical composition of B. trimera show that this plant has bioactive compounds such as flavonoids, related to the organism’s protection against free radicals. Therefore, in the present study, using Fischer rats, the effect of B. trimera on the antioxidant defense system, the production of nitric oxide (NO) and on the expression of nitric oxide synthase (iNOS), superoxide dismutase (SOD), catalase (CAT) and of the subunits of the NADPH oxidase in neutrophils was evaluated in a model of phagocytosis induced by zimosan (ZC3b) and in a model of inflammation induced by acetaminophen. The results show that the treatment with B. trimera improves the defense system of antioxidant and restores the balance ROS / NO that is altered in the inflammatory process induced by APAP. In conclusion, B. trimera extracts exert antioxidant properties by scavenging ROS and decrease the expression of genes responsible by reactive species production in neutrophils.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that decreases postprandial glycemic excursions by enhancing insulin secretion but with short half-life due to rapid inactivation by enzymatic N-terminal truncation. Therefore, efforts are being made to improve the stability of GLP-1 via modifying its structure or inhibiting dipeptidylpeptidase IV (DPP IV), which is responsible for its degradation. GLP-M, consisting of 10 tandem repeated rolGLP-1 (GLP-1 analog), has been expressed in Pichia pastoris by our laboratory. Although it had a long effect of maintaining glucose homeostasis, redundant amino acids and purification tag limited its application. Here, optimized rolGLP-1(GLPO) with no redundant amino acids and purification tag was constructed by molecular cloning and site-directed mutagenesis, which was expressed efficiently in Escherichia coli BL21(DE3) with the production of 81.5 mg/L, and confirmed by the results of SDS-PAGE electrophoresis and Western Blotting. Then GLP-O was purified via ion exchange chromatography and gel filtration chromatography. The purity of GLP-O was close to 100%. GLP-O could be cut into single rolGLP-1 by trypsin in vitro, and rolGLP-1 had anti-trypsin activity. After oral administration of GLP-O for 4 weeks, the level of blood glucose in type 2 diabetic mice was lowered effectively, and the oral glucose tolerance of mice was improved significantly. These results settled the foundation for further clinical application of GLP-O.

Currently dengue is a serious disease which has become a global burden in the last decade. Unfortunately, there are no effective drugs and vaccines against this disease. DENV non-structural protein (NS) 3, which is viral protease which is a potential target for antiviral therapy. Targeting this we performed homology modeling and protein-protein docking study of NS3 with NRBP (Nuclear Receptor Binding Protein) of human as it has been proved that NS3 of DENV interacts with NRBP which causes cellular trafficking in human cell. To carry out search of novel DENV protease inhibitors by in silico screening panduratin molecule was selected. 65 novel compounds were designed which involved substituting positions 1-5 of the benzyl ring A (4hydroxy-panduratinA) with various substituents. The protein-protein docking showed that the aminoacid residues of NS3 which were interacting with NRBP were found to be Ala 325, Asp 324, Phe 326, Asp 335, Glu 336, Glu 328, Asp 485, Gln 478, Arg 459, Gly 446 and Leu 480. These residues were targeted by the ligands which showed excellent binding affinity as binding energy. The ligand PKP10 showed lowest binding energy. It is also observed that the interface residues participated in the protein-protein interaction are being inhibited by the ligands.