Anti-HIV-screening

The National Cancer Institute (NCI) database is a collection of more than half a million structures, assembled by NCI s Developmental Therapeutics Program (DTP) or its predecessors in the course of NCTs anti-cancer screening efforts that started in the late 1950s (plus the more recent anti-HIV screening) [37-39]. Approximately half of this database is publicly available without any usage restrictions, and is therefore called the "Open NCI Database. For each of these structures (more than 250 000) the DTP record contains at least the chemical structure as a coimection table and an NCI accession number, the NSC number. 

Antiviral agents (qv) (15—17) are used in attempts to combat the devastating effect of HIV on the immune system. As of this writing there are three principal approaches to the treatment of AIDS (/) use of anti-HIV agents to destroy the virus or control its growth the National Cancer Institute (NCI) encourages submission of synthetic and characterized natural products for anti-HIV screening (18) (2) immunotherapy to restore impaired immune functions and (3) treatment of specific opportunistic infections or tumors. 

DCK (2) showed extremely increased potency in the anti-HIV screening therefore, it became the new lead in the search for optimal synthetic method, SAR modifications. 

This assay was developed and used in anti-HIV screening programs (Pauwels et al. 1988). The tetrazolium salt MTT [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide] is converted to dark blue formazan by living cells but not by dead cells or culture medium. These assays are carried out in 96-well plates. 

Between 1987 and 1996, the NCI tested over 30 000 plant extracts in an in vitro cell-based anti-HIV screen (http //www.niaid.nih.gov), which determined the degree of HIV-1 replication in treated infected lymphoblastic cells versus that in treated uninfected control cells. Several natural products showed in vitro activity and michellamine B, the calanolides, and prostratin are discussed below. 

Unlike other sulfated sterols of marine origin, the AB and carolisterols (42,43) isolated from Styracaster caroli spp. have not shown any protection against the cytopathic effects of HIV-1 in NCI s primary anti-HIV screen (34). 

These sterol sulfate esters show activity in a number of enzyme and receptor-binding assays and are also active in the anti-HIV screen run at the US National Cancer Institute. A dereplication scheme for this class of compounds has been published by Cardellina et al. (36), in which extracts are chromatographed in three systems Sephadex G-25 for molecular weight C4 wide pore (300) and CIS narrow pore (60 A). Fractions are assayed against HIV and the patterns of activity compared to that observed for halistanol sulfate. Sterol sulfates from six sponge extracts were eluted with methanol H20 (2 1 v/v) and allowed for the rapid dereplication of this class of compound. In... 

The HEPT and TIBO derivatives were discovered as the result of a systematic evaluation for anti-HIV activity in cell culture. They were later found to achieve their anti-HIV-1 activity through an interaction with the HIV-1 RT. In contrast, nevirapine, pyridinone, and BHAP emerged from a screening program for HIV-1 RT inhibitors. The anti-HIV-1 activity of these compounds was subsequently confirmed in cell culture. Like the HEPT and TIBO derivatives, the 2, 5 -bis-0-(tert-butyldimethylsilyl)-3 -spiro-5" -(4" -amino-1", 2" -oxathiole-2", 2" -dioxide)-pyrimidine (TS AO) derivatives (Fig. 9) [65,66] and a-anilinophenylacetamides (a-APA) (Fig. 10) [67] were discovered through the evaluation of their anti-HIV activity in cell culture. Subsequently, they were found to act as specific inhibitors of HIV-1 RT. 

Emphasis in the initial phase of our work was placed on sulfated polysaccharides that are antiviral. Not only were the desired rheological properties and long-term stability achieved in DCE formulations, the activity of the dextran sulfate or N9 were not compromised. DCE formulations containing DS display strong anti-HIV activity in vitro in comparison with negative (not shown) and positive controls (Figure 2). This is an important first step in the screening process towards clinical effectiveness. 

Tamura, S.Y., Bacha, P.A., Gruver, H.S., and Nutt, R.F. Data analysis of high-throughput screening results application of multidomain clustering to the NCI anti-HIV data set./. Med. Chem. 2002, 45, 3082-3093. 

Histaglobulin is thoroughly screened for hepatitis B surface antigen and anti HIV using third generation technique RIA and ELISA and is found to be non-reactive. 

Anti-HIV activity of prenylflavones from mulberry tree, kuwanon H (2), morusin (3) and its derivatives, was reported by Luo et al. [117]. We studied the effect of Morns flavones on HIV-1 ms infected MT-4 cells, but no flavone showed anti-HIV activity in our screening system [111]. These discrepant results might be due to multiple acting sites of... 

Detecting exposure to HIV ELISA assays and western blots are commonly used to detect exposure to HIV by measuring the amount of anti-HIV antibodies present in a patient s blood sample. ELISA assays are used as the primary screening tool, because they are very sensitive. These assays sometimes give false-posi-tives, however, so western blots, which are more specific, are often used as a confirmatory test (Figure 32.23). [Note ELISA and western blots can only detect HIV exposure after anti-HIV antibodies appear in the bloodstream. PCR-based testing for HIV is more useful in the first few months after exposure.]... 

In collaboration with University of Trieste, we have developed rational approaches for the design and synthesis of peptidomimetic and non-peptidic inhibitors of HIV PR, utilizing structure-based [12-15], as well as combinatorial, library design methods [16, 17]. In this paper, we survey computer-assisted studies on the design, focusing and in silico screening of virtual combinatorial libraries of peptidomimetics and cyclic ureas, as potential anti-HIV agents, that were carried out in our laboratory. 

HIV-2 HIV-2, which is closely related to HIV-1, was first reported to be associated with AIDS in 1986 in West Africa, where it is believed to be endemic. Several cases of HIV-2 infection have been reported among Europeans and West Africans residing in Europe and in the USA. The spectrum of disease and modes of transmission of HIV-2 seem to be similar to those of HIV-1 (182). However, there have been only relatively few reports of HIV-2 transmission in blood. The anti-HIV-1 El A tests currently used for screening blood donors are estimated to detect from 42 to 92% of HIV-2 infections (183). Anti-HIV-2 assays are available and are used routinely in blood donor screening. 

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