HIV-1 Integrase Drug Discovery Comes of Age

Insertion of the viral genome into host cell chromatin is a pivotal step in the replication cycle of the human immunodeficiency virus and other retroviruses. Blocking the viral integrase enzyme that catalyzes this reaction therefore provides an attractive therapeutic strategy. Nevertheless, many years lie between the initial discovery of integrase and the clinical approval of the first integrase strand transfer inhibitor, raltegravir, in 2007. Recently, elvitegravir was second to make it into the clinic, while dolutegravir, a second-generation integrase inhibitor, is close to receiving the green light as well. Viral resistance and cross-resistance among these strand transfer inhibitors however warrant the search for compounds targeting HIV integration through different mechanisms of action. The most advanced class of allosteric integrase inhibitors, coined LEDGINs or non-catalytic integrase inhibitors (NCINIs), has shown remarkable antiviral activity that extends beyond the viral integration step. Time will tell however if they will stand the test of clinical development. Notably, the development of LEDGINs and other integrase inhibitors is aided by recent structural and mechanistic insights into the retroviral integration apparatus. Here we provide an overview of the development of integrase strand transfer and allosteric inhibitors while exploring their mechanisms of action and patterns of viral resistance.status: publishe

Behavioural Studies in Spatial Planning

The main strategic planning policy in Flanders has in view to reduce the growth of the net settlement area. It is important to enthuse people to live closer together in the centres of villages, towns or in more dense urban areas to preserve open areas. The question is how to achieve this.In the last few years, there has been a growing awareness of the importance of convincing citizens to change their behaviour voluntarily. A crucial question is which behavioural change we can expect from the population, whether this can be met at once by everyone and what a government has to change or needs to provide to make the change possible. In recent years, the Flemish Planning Bureau for the Environment and Spatial Development commissioned several behavioural studies, conducted by Endeavour. It concerns two studies carried out on compact housing, on travel behaviour, on choice of residence in relation to facilities, and a new study on the behavioural influencers of housing. Thanks to an approach that combines the fields of architecture, urban planning, sociology and design Endeavour created a methodology of participation and co-creation with citizens, aiming at different segmentations of the population. This method successfully brought a multitude of experiences to the surface by means of a variety of people who sufficiently represent the diversity in Flanders. Insights into attitudes and motivations of a broad public are the key to understanding how to change certain aspects of behaviour into something more sustainable. This paper focuses on two themes. The first reflects on practices, tools and knowledge that are nowadays common in (regional) spatial planning and how they relate to human behaviour. The second introduces insights from qualitative research for behavioural change that focuses on how to approach different target groups within the population. The aim is to guide behaviour in function of an inclusive and sustainable spatial transition. As the paper shows, it is important that in this transition process people do not get the feeling of 'losing' something. such as comfort or choice

Fueling HIV-1 integrase drug design with structural insights

Integrase (IN) is the last of the three Human Immunodeficiency Virus-1 (HIV-1) enzymes to be targeted by antiretroviral therapy. At present, a single integration inhibitor (raltegravir) has been approved for clinical use. Rapid emergence of drug resistance warrants development of novel inhibitors. Fortunately, the past few years have brought forth a tremendous increase in the understanding of the molecular and structural biology of integration. We discuss recent discoveries as well as novel opportunities for structure-based design in the quest for novel IN inhibitors. © 2012 Elsevier Ltd. All rights reserved.status: publishe

HIV-1 integrase variants retarget viral integration on both a local as well as on a global scale

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Targeting the collagen – von Willebrand factor – Glycoprotein Ibα binding axis with structure-based drug design

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The Feasibility of Tracheal Oxygen Supplementation during Flexible Bronchoscopy

Background: Hypoxemia is a frequent adverse event occurring during flexible bronchoscopy and is usually prevented by close monitoring and, if needed, oxygen supplementation by nasal cannula. Objective: We aim to demonstrate that tracheal oxygen supplementation during flexible bronchoscopy is a feasible, safe and effective method to restore oxygen saturation levels after oxygen desaturation. Methods: In a first phase, we compare oxygen supplementation by the tracheal or nasal route in a single blinded cross-over design in healthy volunteers. In a second phase, we study patients referred for diagnostic flexible bronchoscopy, who desaturate despite oxygen supplementation by nasal cannula, in order to assess the ability to correct hypoxemia through tracheal oxygen supplementation. Results: In the first phase, the mean capillary partial pressure of oxygen was 181 mm Hg when oxygen at a flow rate of 4 liters/min was administered by the tracheal route, compared to 125 mm Hg by the nasal route (p < 0.001). The capillary partial pressure of carbon dioxide was not significantly different. During 950 bronchoscopic procedures in the second phase of the trial, 30 patients desaturated below 90% despite oxygen supplementation by nasal cannula. In 22 out of these 30 patients, switching to the tracheal route resulted in a correction of the saturation within 120 s. In the remaining 8 patients, saturation levels were corrected after increasing the oxygen flow rate to 4 liters/min. After restoring saturation levels, the bronchoscopy could be completed in 25 of 30 patients. Conclusions: Tracheal oxygen supplementation is safe, feasible and an effective way to restore oxygen saturation levels during flexible bronchoscopy.SCOPUS: ar.jinfo:eu-repo/semantics/publishe