Characterization of STP0404 resistant viral replication kinetics, efficacy against common polymorphisms, antiviral efficacy of enantiomers, and X-ray structure of IN CCD–STP0404 complex.
2021
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Zugriff:
A. Replication kinetics of STP0404 resistant HIV-1 variants in CEMx174 cells. p24 levels of wild type (WT) HIV-1 89.6 or indicated IN variant in the collected culture media are noted. Fold differences of the variants in p24 levels, compared to wild type virus culture at day 4 were calculated. B. IC 50 values of STP0404 against wild type HIV-1 89.6 or indicated IN variants in CEMx174 cells. C. IC 50 values of (R) and (S) enantiomers of STP0404 against wild type HIV-1 89.6 in CEMx174 cells were determined, and their fold differences were calculated. Data in panels a-c are presented as means of triplicates and error bars indicate the standard deviations from the means. D. X-ray structure of HIV-1 IN CCD dimer bound to STP0404 (yellow/mesh). Two interacting CCDs are colored green (subunit 1) and cyan (subunit 2). Fo-Fc omit map calculated while omitting STP0404 is contoured at 3σ at resolution of 2.2 Å. A close up of STP0404 (mesh) binding to the LEDGF/p75 binding pocket was shown in S2 Fig . E. Superposition of our STP0404 structure (yellow, PDB: 7KE0) with quinoline based BI-D (pink, PDB: 4ID1) and pyridine based KF116 (gray, PDB: 4O55). F. Principal STP0404 interactions with the CCD-CCD dimer. W132, E170, H171 and T174 side chains are shown as sticks. Dashed lines indicate hydrogen bonding contacts. G. The side chains of A128 and Y99 are shown in the context of bound STP0404. Data collection and refinement statistics are described in S1 Table .
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Characterization of STP0404 resistant viral replication kinetics, efficacy against common polymorphisms, antiviral efficacy of enantiomers, and X-ray structure of IN CCD–STP0404 complex.
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Autor/in / Beteiligte Person: | Tatsuya Maehigashi (1344159) ; Seohyun Ahn (11172117) ; Uk-Il Kim (11172120) ; Jared Lindenberger (11172123) ; Adrian Oo (11172126) ; Pratibha C. Koneru (6298775) ; Bijan Mahboubi (5853317) ; Alan N. Engelman (795355) ; Mamuka Kvaratskhelia (43017) ; Kyungjin Kim (140317) ; Baek Kim (66773) |
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Veröffentlichung: | 2021 |
Medientyp: | Bild |
DOI: | 10.1371/journal.ppat.1009671.g003 |
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