Nanovaccines and their mode of action.

Nanosized particles including nanovaccines are a novel approach to the development of vaccines to combat diseases. Nanovaccines have the promise to utilize the immune system to cure infections and to prevent infections and diseases from spreading. Rational vaccine development requires an understanding of vaccine mediated stimulation of the immune system.

Strategies for intranasal delivery of vaccines.

The vast majority of human pathogens colonize and invade at the mucosal surfaces. Preventing infection at these sites via mucosally active vaccines is a promising and rational approach for vaccine development. However, it is only recently that the stimulation of local immunity at the mucosal surfaces has become a primary objective in addition to inducing systemic immunity.

The Effect of Environment on the Structure of a Membrane Protein: P-Glycoprotein under Physiological Conditions.

The stability of the crystal structure of the multidrug transporter P-glycoprotein proposed by Aller et al. (PDBid 3G5U ) has been examined under different environmental conditions using molecular dynamics. We show that in the presence of the detergent cholate, the structure of P-glycoprotein solved at pH 7.

Design of fully synthetic, self-adjuvanting vaccine incorporating the tumor-associated carbohydrate Tn antigen and lipoamino acid-based Toll-like receptor 2 ligand.

Overexpression of certain tumor-associated carbohydrate antigens (TACA) caused by malignant transformation offers promising targets to develop novel antitumor vaccines, provided the ability to break their inherent low immunogenicity and overcome the tolerance of the immune system. We designed, synthesized, and immunologically evaluated a number of fully synthetic new chimeric constructs incorporating a cluster of the most common TACA (known as Tn antigen) covalently attached to T-cell peptide epitopes derived from polio virus and ovalbumin and included a synthetic built-in adjuvant consisting of two 16-carbon lipoamino acids. Vaccine candidates were able to induce significantly strong antibody responses in mice without the need for any additional adjuvant, carrier protein, or special pharmaceutical preparation (e.

Missing fragments: detecting cooperative binding in fragment-based drug design.

The aim of fragment-based drug design (FBDD) is to identify molecular fragments that bind to alternate subsites within a given binding pocket leading to cooperative binding when linked. In this study, the binding of fragments to human phenylethanolamine N-methyltransferase is used to illustrate how (a) current protocols may fail to detect fragments that bind cooperatively, (b) theoretical approaches can be used to validate potential hits, and (c) apparent false positives obtained when screening against cocktails of fragments may in fact indicate promising leads.

Immunological evaluation of lipopeptide group A streptococcus (GAS) vaccine: structure-activity relationship.

Streptococcus pyogenes (group A streptococcus, GAS) is a Gram-positive bacterial pathogen responsible for a wide variety of diseases. To date, GAS vaccine development has focused primarily on the M-protein. The M-protein is highly variable at the amino (N)-terminus (determining serotype) but is conserved at the carboxyl (C)-terminus.

Using Theory to Reconcile Experiment: The Structural and Thermodynamic Basis of Ligand Recognition by Phenylethanolamine N-Methyltransferase (PNMT).

A fundamental challenge in computational drug design is the availability of reliable and validated experimental binding and structural data against which theoretical calculations can be compared. In this work a combination of molecular dynamics (MD) simulations and free energy calculations has been used to analyze the structural and thermodynamic basis of ligand recognition by phenylethanolamine N-methyltransferase (PNMT) in an attempt to resolve uncertainties in the available binding and structural data. PNMT catalyzes the conversion of norepinephrine into epinephrine (adrenaline), and inhibitors of PNMT are of potential therapeutic importance in Alzheimer's and Parkinson's disease.

Molecular field analysis (MFA) and other QSAR techniques in development of phosphatase inhibitors.

Phosphatases are well known drug targets for diseases such as diabetes, obesity and other autoimmune diseases. Their role in cancer is due to unusual expression patterns in different types of cancer. However, there is strong evidence for selective targeting of phosphatases in cancer therapy.

Synthesis of the sponge-derived plakortone series of bioactive compounds.

The Caribbean sponges of the genus Plakortis, P. halichondrioides, and P. simplex have provided a series of biologically active furanolactones-the plakortones A-D (1-4) from the former sponge and B-F (2-6) from the latter.