http://www.bio-medicine.org/biology-news-1/Ne...r-deadly-viruses-28823-1/

"Date:2/11/2013

Newly identified natural protein blocks HIV, other deadly viruses

A team of UCLA-led researchers has identified a protein with broad virus-fighting properties that potentially could be used as a weapon against deadly human pathogenic viruses such as HIV, Ebola, Rift Valley Fever, Nipah and others designated "priority pathogens" for national biosecurity purposes by the National Institute of Allergy and Infectious Disease.

In a study published in the January issue of the journal Immunity, the researchers describe the novel antiviral property of the protein, cholesterol-25-hydroxylase (CH25H), an enzyme that converts cholesterol to an oxysterol called 25-hydroxycholesterol (25HC), which can permeate a cell's wall and block a virus from getting in.

Interestingly, the CH25H enzyme is activated by interferon, an essential antiviral cell-signaling protein produced in the body, said lead author Su-Yang Liu, a student in the department of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA..."

http://www.bio-medicine.org/biology-news-1/St...y-news+%28Biology+News%29

"Date:1/21/2013

Stopping smoking reduces risk of bacterial pneumonia in people with HIV

Bacterial pneumonia is one of the commonest and most serious infections occurring in people infected with HIV. A metanalysis of cohort and case control studies published in BioMed Central's open access journal BMC Medicine finds that current smokers with HIV were at double the risk of bacterial pneumonia than non-smoking counterparts, but that when people stopped smoking their risk was reduced.

The metanalysis reanalysed the data of several thousand participants with HIV, from 14 studies based in USA, Europe and South Africa. Overall it appeared that current smoking was associated with a 70-100% increase in risk of bacterial pneumonia, compared to non-smokers, but that stopping smoking decreased this by about a third. This was independent of CD4 count or antiretroviral therapy..."

As one of the key research areas of the WCG Fight Against Aids project concerns research into possible Allosteric HIV replication inhibitors, I thought posting some articles I found on this subject might be of interest. The appended article is available for public access.

I apologize advance if they have been previously posted.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115487/

"Published online 2011 January 12.

ChemMedChem. 2011 February 7; 6(2): 228–241.

Allosteric Inhibitor Development Targeting HIV-1 Integrase

Laith Q. Al-Mawsawi* and Nouri Neamati*

HIV-1 integrase (IN) is one of three essential enzymes for viral replication, and a focus of ardent antiretroviral drug discovery and development efforts. Diligent research has led to the development of the strand transfer specific chemical class of IN inhibitors, with two compounds from this group, raltegravir and elvitegravir, advancing the farthest in the US FDA approval process for any IN inhibitor discovered thus far. Raltegravir, developed by Merck & Co., has been US FDA approved for HIV-1 therapy, whereas elvitegravir, developed by Gilead Sciences and Japan Tobacco, has reached Phase III clinical trials. Although this is an undoubted success for the HIV-1 IN drug discovery field, the development of HIV-1 IN strand transfer specific drug resistant viral strains upon clinical use of the compounds is expected in the patient. Furthermore the problem of strand transfer specific IN drug resistance will be exacerbated by the development of cross-resistant viral strains due to an overlapping binding orientation at the IN active site and an equivalent inhibitory mechanism for the two compounds. This inevitability will result in no available IN-targeted therapeutic options for HIV-1 treatment experienced patients. The development of allosterically targeted IN inhibitors presents an extremely advantageous approach for the discovery of compounds effective against IN strand transfer drug resistant viral strains, and would likely show synergy with all available FDA approved antiretroviral HIV-1 therapeutics, including the IN strand transfer specific compounds. Here we review the concept of allosteric IN inhibition, and the small molecules that have been investigated to bind non-active site regions to inhibit IN function..."


ChemMedChem. 2011 February 7; 6(2): 228–241.

http://pubs.acs.org/doi/full/10.1021/jm1010513

"J. Med. Chem., 2011, 54 (3), pp 699–708
DOI: 10.1021/jm1010513
Publication Date (Web): January 5, 2011

A novel scaffold inhibiting wild type and drug resistant variants of human immunodeficiency virus type 1 reverse transcriptase (HIV-1RT) has been identified in a library consisting of 1040 fragments. The fragments were significantly different from already known non-nucleoside reverse transcriptase inhibitors (NNRTIs), as indicated by a Tversky similarity analysis. A screening strategy involving SPR biosensor-based interaction analysis and enzyme inhibition was used. Primary biosensor-based screening, using short concentration series, was followed by analysis of nevirapine competition and enzyme inhibition, thus identifying inhibitory fragments binding to the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Ten hits were discovered, and their affinities and resistance profiles were evaluated with wild type and three drug resistant enzyme variants (K103N, Y181C, and L100I). One fragment exhibited submillimolar KD and IC50 values against all four tested enzyme variants. A substructure comparison between the fragment and 826 structurally diverse published NNRTIs confirmed that the scaffold was novel. The fragment is a bromoindanone with a ligand efficiency of 0.42 kcal/mol−1..."

http://www.jbc.org/content/early/2012/03/21/jbc.M112.354373

"A multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors

Jacques J. Kessl1, Nivedita Jena1, Yasuhiro Koh2, Humeyra Taskent-Sezgin3,
Alison Slaughter4, Lei Feng4, Suresh de Silva4, Li Wu4, Stuart F. J. Le Grice3,
Alan Engelman2, James R. Fuchs4 and Mamuka Kvaratskhelia1,*

The multifunctional HIV-1 enzyme integrase (IN) interacts with viral DNA and its key cellular cofactor LEDGF to effectively integrate the reverse transcript into a host cell chromosome. These interactions are crucial for HIV-1 replication and present attractive targets for antiviral therapy. Recently, 2-(quinolin-3-yl) acetic acid derivatives were reported to selectively inhibit the IN-LEDGF interaction in vitro and impair HIV-1 replication in infected cells. Here we show that this class of compounds impairs both IN-LEDGF binding and LEDGF-independent IN catalytic activities with similar IC50 values, defining them as bona fide allosteric inhibitors of IN function. Furthermore, we show that 2-(quinolin-3-yl) acetic acid derivatives block the formation of the stable synaptic complex (SSC) between IN and viral DNA by allosterically stabilizing an inactive multimeric form of IN. In addition, these compounds inhibit LEDGF binding to the SSC. This multimode mechanism of action concordantly results in cooperative inhibition of the concerted integration of viral DNA ends in vitro and HIV-1 replication in cell culture. Our findings, coupled with the fact that high cooperativity of antiviral inhibitors correlates with their increased instantaneous inhibitory potential, an important clinical parameter, argue strongly that improved 2-(quinolin-3-yl) acetic acid derivatives could exhibit desirable clinical properties..."