Structural Optimization and De Novo Design of Dengue Virus Entry Inhibitory Peptides

Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By using predictive strategies together with computational optimization of binding “pseudoenergies”, we were able to design multiple peptide sequences that showed low micromolar viral entry inhibitory activity. The two most active peptides, DN57opt and 1OAN1, were designed to displace regions in the domain II hinge, and the first domain I/domain II beta sheet connection, respectively, and show fifty percent inhibitory concentrations of 8 and 7 µM respectively in a focus forming unit assay. The antiviral peptides were shown to interfere with virus:cell binding, interact directly with the E proteins and also cause changes to the viral surface using biolayer interferometry and cryo-electron microscopy, respectively. These peptides may be useful for characterization of intermediate states in the membrane fusion process, investigation of DENV receptor molecules, and as lead compounds for drug discovery

What constitutes the best sex life for gay and bisexual men? Implications for HIV prevention.

BACKGROUND: While a large body of research has sought to understand HIV transmission risk behaviours among gay men, bisexual men and other men who have sex with men (MSM), less attention has been paid to the wider sexual health and well-being of this population. While some community-based organisations aim to support a more holistic sense of sexual well-being there is little evidence to draw on to inform their interventions. The current study sought to explore gay and bisexual men's conceptions of what constitutes the 'best sex'. METHOD: The EMIS survey of 2010 recruited more than 180,000 respondents from 38 European countries to complete an online questionnaire about sexual health and behaviour. The 12,942 English language, UK-based responses to the open ended question, "What's your idea of the best sex life?" were subjected to a detailed content analysis. A framework was devised to reflect and describe the key themes emerging from the data, which was then used to code all responses to one (or more) of these themes. Further statistical analysis sought to establish if and how responses differed according to key demographic variables. RESULTS: Eight themes emerged that capture the diversity of gay and bisexual men's sexual desires. Most common among responses was a desire for sex within committed relationships, followed by a desire for sex which is emotionally or psychologically connected. Men also expressed a desire for volume and variety in their sexual lives, and for sex that is free from physical, social or psychological harm. Comparative analysis identified that older men were less likely to idealise a relationship or emotional connection, but were more likely to specify the sexual acts or behaviours they wished to engage in. CONCLUSIONS: Attending to what men value or aspire to can help ensure interventions are engaging and meaningful to the target population. HIV prevention interventions need to attend to the broad range of sexual desires held by gay and bisexual men in delivery of holistic sexual health promotion that can help them to have the best sex with the least harm