Computer-aided design, synthesis, and biological activity evaluation of potent fusion inhibitors targeting HIV-1 gp41.

This discovered and optimized several novel HIV-1 fusion inhibitors and further evaluated the inhibitory activities of these compounds in vitro. Here, we have reported the computer-aided design, synthesis, and biological evaluation of a series of small molecule fusion inhibitors targeting HIV-1 gp41. Based on the structure of inhibitor (NB2), we carried out de novo design and screened out a series of novel structure molecules by using Leapfrog and Autodock programs. Our structure-based modification obtained a potent fusion inhibitor (IC50 = 41.1 µg/mL). Several novel compounds were discovered as fusion inhibitors, which suggested that our design methodology is reliable, paving the way for de novo design of novel small-molecule HIV inhibitors targeting gp41.

[Effect of pre-electroacupuncture at "Zusanli" (ST 36) on DA and 5-HT contents and their ratio in hypothalamus and striatum in exercise rats].

OBJECTIVE: To observe anti-fatigue effect and mechanisms of pre-electroacupuncture (EA) at "Zusanli" (ST 36) in rats undergoing acute treadmill running. METHODS: Fifty male SD rats were randomly divided into three groups: a quiet group (group Q, n = 10), a model group (group M, n = 20) and an EA preconditioning group (group EAP, n = 20). After adaptation for undergoing treadmill running, all the rats in group M and group EAP were trained on acute treadmill running. Besides, EA with continuous waves, 2 Hz in frequency and 2 mA in intensity was applied at bilateral "Zusanli" (ST 36) for 30 min, which was applied once daily for continuous 6 days before treadmill running for the rats in Group EAP. Plasma lactate contents were measured immediately and 3 hours after treadmill running, respectively. Changes of dopamine (DA) and serotonin (5-HT) contents obtained immediately and 3 hours after treadmill running, respectively, in hypothalamus and striatum, were detected and compared, and DA/5-HT ratios were calculated. RESULTS: Compared with group Q, the levels of blood lactate and hypothalamic 5-HT tented to increase in rats of group M, and the contents of hypothalamic DA increased significantly (P < 0.01), while the contents of striatal DA and 5-HT in group M decreased significantly (both P < 0.01) at 3 h after treadmill running. Immediately after treadmill running, the contents of DA and 5-HT increased significantly in hypothalamus (both P < 0.01), but decreased significantly in striatum (both P < 0.01) in group EAP, compared with those in group M. Moreover, EA pretreatment markedly decreased the levels of blood lactate (P < 0.05) and hypothalamic 5-HT (P < 0.01), and obviously elevated the ratio of DA/5-HT in the hypothalamus (P < 0.01) at 3 h after treadmill running. CONCLUSION: Preventive EA at "Zusanli" (ST 36) can accelerate recovery from fatigue, which may be related to its reducing accumulation of blood lactate, elevating DA/ 5-HT ratio in the hypothalamus of the rats undergoing treadmill running.

Design, synthesis and anti-HIV integrase evaluation of N-(5-chloro-8-hydroxy-2-styrylquinolin-7-yl)benzenesulfonamide derivatives.

Styrylquinoline derivatives are demonstrated to be HIV-1 integrase inhibitors. On the basis of our previous CoMFA analysis of a series of styrylquinoline derivatives, N-[(2-substituted-styryl)-5-chloro-8-hydroxyquinolin-7-yl]-benzenesulfonamide derivatives were designed and synthesized,and their possible HIV IN inhibitory activity was evaluated.

[Effects of transcutaneous electric acupoint stimulation on plasma SOD and MDA in rats with sports fatigue].

OBJECTIVE: To observe the effect of transcutaneous electric acupoint stimulation (TEAS) on plasma superoxide dismutase (SOD) and malondialdehyde (MDA) in rats with sports fatigue so as to explore its mechanisms in resisting exercise-induced fatigue. METHODS: Twenty-seven male adult SD rats were randomly divided into control group (n 9), model group (n=9) and TEAS group (n=9). Sports fatigue model was established by using treadmill method, i.e. forcing the rat to run 10 min at a speed of 10 m/min, 15 m/min, 20 m/min, 24 m/min and 28 m/min, once daily for 6 days. TEAS (continuous waves, 2 Hz, 5 mA) was applied to unilateral "Zusanli" (ST 36) for 30 min, once per day for 7 days. The exhausted exercise time from starting running to exhaustion was recorded on the 7th day and the lactate levels, SOD activity and MDA contents in plasma were measured by lactate oxidase method, xanthine oxidase method and thiobarbituric acid method respectively. RESULTS: The duration of exhausted exercise in model group and TEAS group were (56.00 +/- 12.27) min and (70.88 +/- 13.74) min respectively, displaying significant increase in exercise tolerance after TEAS (P<0.05). The lactate level and MDA content in model group were markedly higher than those in control group (P<0.05); while compared with model group, lactate and MDA contents in TEAS group were significantly lower (P<0.05), and plasma SOD activity in TEAS group was significantly higher (P<0.01). No significant differences were found in plasma lactate content between control and TEAS groups and in SOD activity between model group and control group (P>0.05). SOD/MDA of model group was significantly lower than those of control group and TEAS group (P<0.05, 0.01). CONCLUSION: TEAS at "Zusanli"(ST 36) can effectively postpone exercise-induced fatigue by reducing accumulation of blood lactate, improving anti-oxidative ability and relieving lipid peroxidation in the rat.

A novel high-throughput format assay for HIV-1 integrase strand transfer reaction using magnetic beads.

AIM: To develop a novel high-throughput format assay to monitor the integrase (IN) strand transfer (ST) reaction in vitro and apply it to a reaction character study and the identification of antiviral drugs. METHODS: The donor DNA duplex, with a sequence identical to the U5 end of HIV-1 long terminal repeats, is labeled at its 5' end with biotin (BIO). The target DNA duplex is labeled at its 3' end with digoxin (DIG). IN mediates the integration of donor DNA into target DNA and results in a 5' BIO and 3' DIG-labeled duplex DNA product. Streptavidin-coated magnetic beads were used to capture the product, and the amount of DIG was measured as the ST reaction product. The assay was optimized in 96-well microplate format for high-throughput screening purpose. Moreover, the assay was applied in a ST reaction character study, and the efficiency of the assay in the identification of antiviral compounds was tested. RESULTS: The end-point values, measured as absorbance at 405 nm was approximately 1.5 for the IN-mediated ST reaction as compared with no more than 0.05 of background readings. The ST reaction character and the half maximal inhibitory concentration (IC50) values of 2 known IN inhibitors obtained in our assay were similar to previously reported results using other assays. The evaluation parameter Z' factor for this assay ranged from 0.6 to 0.9. CONCLUSION: The assay presented here has been proven to be rapid, sensitive, and specific for the detection of IN ST activity, the reaction character study, as well as for the identification of antiviral drugs targeting IN.