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Tatsuya Maehigashi Seohyun Ahn Uk-Il Kim Jared Lindenberger Adrian Oo Pratibha C. Koneru Bijan Mahboubi Alan N. Engelman Mamuka Kvaratskhelia Kyungjin Kim Baek Kim 《PLoS pathogens》2021,17(7)
Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC50 in human PBMCs with a >24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF/p75 binding pocket render resistance to STP0404. Extensive in vivo pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF/p75 binding site and has advanced to a human trial. 相似文献
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In this genomics and proteomics age, highly functionalized natural products or natural-product-like compounds are likely to play important roles in understanding the functions of emerging biological targets because they serve as small-molecule chemical probes in modulating a target's specific actions (i.e. activation or deactivation). Development of stereoselective reaction-derived methods on solid phase provides a means of obtaining functionalized chiral core structures that may be used for high-throughout syntheses. 相似文献
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Control of chromosome replication involves a common set of regulators in eukaryotes, whereas bacteria with divided genomes use chromosome-specific regulators. How bacterial chromosomes might communicate for replication is not known. In Vibrio cholerae, which has two chromosomes (chrI and chrII), replication initiation is controlled by DnaA in chrI and by RctB in chrII. DnaA has binding sites at the chrI origin of replication as well as outside the origin. RctB likewise binds at the chrII origin and, as shown here, to external sites. The binding to the external sites in chrII inhibits chrII replication. A new kind of site was found in chrI that enhances chrII replication. Consistent with its enhancing activity, the chrI site increased RctB binding to those chrII origin sites that stimulate replication and decreased binding to other sites that inhibit replication. The differential effect on binding suggests that the new site remodels RctB. The chaperone-like activity of the site is supported by the finding that it could relieve the dependence of chrII replication on chaperone proteins DnaJ and DnaK. The presence of a site in chrI that specifically controls chrII replication suggests a mechanism for communication between the two chromosomes for replication. 相似文献
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The life history traits of the caddisfly, Psilotreta locumtenens Botosaneanu (Odontoceridae), were studied in two stream reaches with different thermal ranges (main and branch streams) of the Gapyeong Stream, a typical mountain stream located in the central Korean Peninsula. Psilotreta locumtenens larvae were quantitatively sampled monthly from November 2008 to July 2010, and biweekly during the emergence period (late April to early July), using a Surber sampler (30 × 30 cm). Adults were quantitatively sampled with a sweep net. Larval density in the main stream (324.21 ± 38.59 m?2) was higher than that in the branch stream (60.48 ± 10.86 m?2). The larvae hatched in the early summer and overwintered as 5th and 3rd instars in the main and branch streams, respectively. The emergence peak at the main stream was approximately 2 weeks earlier. The sex ratio at both sites was approximately 0.3. The life history in both streams was univoltine. Secondary production in the main stream was much higher than in the branch stream, owing to high larval densities, and the P/B ratios at the two sites were similar. This study demonstrated remarkable differences in larval growth patterns and emergence peaks in P. locumtenens between the two stream reaches due to differences in accumulated degree days (230.30 DD) and other phenological cues such as daily mean threshold water temperature (9°C) during the ascending phase, despite their relatively small mean annual water temperature difference of 0.58°C. 相似文献
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Hyun Jung Jho Yeol Kim Kyung Ae Kong Dae Hyun Kim Jin Young Choi Eun Jeong Nam Jin Young Choi Sujin Koh Kwan Ok Hwang Sun Kyung Baek Eun Jung Park 《PloS one》2014,9(8)