Computational design of a sulfoglucuronide derivative fitting into a hydrophobic pocket of dengue virus E protein.

We performed first-principles calculations based on the ab initio fragment molecular orbital method on dengue virus envelope protein with a hydrophobic ligand, octyl-ß-D-glucose to develop an entry inhibitor. As several polar amino acid residues are present at the edge of the pocket, the glucose moiety was chemically modified with hydrophilic groups. Introduction of both sulfated and carboxylated groups on glucose enhanced not only binding affinity to the protein but also inhibition of dengue virus entry. Octyl-2-O-sulfo ß-D-glucuronic acid may serve as a molecular probe to study the dengue virus entry process.

3-O-sulfated glucuronide derivative as a potential anti-dengue virus agent.

A series of 12 carbohydrate compounds were synthesized by introduction of a sulfated group at specific positions and evaluated for their activities against dengue virus (DENV) infection as well as binding to BHK-21 cells. 3-O-sulfated GlcA was active against DENV infection, whereas 2-O-sulfated GlcA and 3,6-di-O-sulfated Glc showed negligible activity. Persulfated compounds did not inhibit DENV infection. These results provided a rationale for designing sulfated carbohydrate compounds with low molecular mass as anti-DENV agents targeting E protein functions. 3-O-Sulfated GlcA showed no significant cytotoxicity at 1mM. The EC(50) value (120 µM) was lower than that of sucrose octasulfate (SOS), a small molecular weight inhibitor of DENV infection. Two negatively charged groups, 3-O-sulfate and 6-C-carboxylic acid, appear to be essential for anti-DENV activity. We performed docking study to investigate the binding potential of 3-O-sulfated GlcA with respect to DENV E protein. The docking study showed that distance and conformation of these negative charges on the carbohydrate may be suitable for association with three amino acid residues of E protein critically involved in virus adsorption (Lys295, Ser145, and Gly159). This interaction may competitively prevent functional DENV binding to receptor(s) on host cells. In conclusion, 3-O-sulfated GlcA is a chemical probe that may facilitate exploration of the molecular mechanisms underlying manifestations of dengue diseases.

Origin of the inhibitory activity of 4-O-substituted sialic derivatives of human parainfluenza virus.

Human parainfluenza virus (hPIV) is a serious human pathogen causing upper and lower respiratory tract disease, yet there are no effective vaccines or therapies to control parainfluenza virus infections. Recently, we found that 4-O-substituted sialic derivatives have potent inhibitory activity against hPIV-1, whereas the anti-influenza inhibitor Zanamivir was less inhibitory. To elucidate the origin of the high potency inhibitory activities of these 4-O-substituted derivatives, we performed correlated fragment molecular orbital (FMO)-interfragment interaction energy (IFIE) analysis for hemagglutinin-neuraminidase (HN) glycoprotein complexes of hPIV with the derivatives and compared them with those for Zanamivir. We found key interactions between the inhibitors and the hPIV HN glycoprotein and identified important factors for the inhibitory activity. These theoretical results will be useful for the development of novel anti-hPIV drugs.