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- Hultén, Johan, et al.
(författare)
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Cyclic HIV-1 protease inhibitors derived from mannitol : synthesis, inhibitory potencies, and computational predictions of binding affinities
- 1997
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40:6, s. 885-897
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Tidskriftsartikel (refereegranskat)abstract
- Ten C-2-symmetric cyclic urea and sulfamide derivatives have been synthesized from L-mannonic gamma-lactone and D-mannitol. The results of experimental measurement of their inhibitory potencies against HIV-1 protease were compared to calculated free energies of binding derived from molecular dynamics (MD) simulations. The compounds were selected, firstly, to enable elucidation of the role of stereochemistry for binding affinity (1a-d) and, secondly, to allow evaluation of the effects of variation in the link to the P1 and P1' phenyl groups on affinity (la and 2-5). Thirdly, compounds with hydrogen bond-accepting or -donating groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a linear response method, whose predictive power for estimating binding affinities from MD simulations was demonstrated.
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- Yilmaz, Aylin, 1974, et al.
(författare)
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Cerebrospinal fluid HIV-1 RNA, intrathecal immunoactivation, and drug concentrations after treatment with a combination of saquinavir, nelfinavir, and two nucleoside analogues: the M61022 study.
- 2006
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Ingår i: BMC infectious diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The way various antiretroviral drugs and drug combinations affect HIV-1 infection in the central nervous system is still largely unknown. The aim of this study was to determine the cerebrospinal fluid (CSF) steady-state concentrations of saquinavir and nelfinavir in relation to plasma concentrations, and to study their effect in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) on CSF viral loads, intrathecal immunoactivation, and blood-brain barrier integrity. METHODS: Paired CSF and plasma samples from 8 antiretroviral-naïve HIV-1 infected patients starting combination therapy with saquinavir, nelfinavir, and two nucleoside analogues were collected prior to treatment, and again after approximately 12 and 48 weeks of antiretroviral therapy. Additional plasma samples were taken at weeks 2, 4, 8, 24, and 36. The concentrations of protease inhibitors were analysed, as were levels of HIV-1 RNA, CD4+ T-cell count, beta2-microglobulin, neopterin, albumin ratio, IgG index, and monocytic cell count. RESULTS: None of the patients in the study presented with HIV-1 RNA < 50 copies/mL in CSF or plasma prior to treatment, compared to 5/7 at the end of the study. Signs of cell-mediated intrathecal immunoactivation, measured by neopterin and beta2-microglobulin, decreased significantly in both CSF and serum, although only 1/7 reached normal CSF neopterin levels after 48 weeks of treatment. There was no significant reduction of albumin ratio, IgG index or CSF monocytic cell count. Saquinavir median (range) concentrations were < 2.5 (< 2.5-96.0) nM unbound in plasma, and < 2.5 (< 2.5-9.0) nM total in CSF. Nelfinavir median (range) concentrations were 10.0 (< 2.0-31.0) nM unbound in plasma, and < 2.0 (< 2.0-23.0) nM total in CSF. Saquinavir and nelfinavir were detectable in 7/15 and 9/15 CSF samples, respectively. CONCLUSION: Saquinavir and nelfinavir, in combination with two NRTIs, decrease the CSF viral load and, to a lesser extent, intrathecal immunoactivation. We found reasonably high CSF concentrations of nelfinavir, but suboptimal concentrations of saquinavir.
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- Zuccarello, Guido, et al.
(författare)
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HIV-1 protease inhibitors based on acyclic carbohydrates
- 1998
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 63:15, s. 4898-4906
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Tidskriftsartikel (refereegranskat)abstract
- A series of acyclic C2-symmetric HIV protease inhibitors readily accessible from D-mannitol have been developed. Several of the compounds synthesized showed significant in vitro activity against HIV-1 protease.
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