Publications

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<title>Abstract</title> Background Having the potential disadvantages and safety risk of the use of anti-HIV-1 drug candidate <bold>K-5a2</bold> in the longterm treatment of HIV patients in mind, we set out with the goal of finding a second-generation backup compound of <bold>K-5a2</bold> with the appropriate anti-HIV potency, significantly reduced hERG activity, decreased induction of the CYP enzyme, and improved aqueous solubility. Herein, using a N-propionylsulfonamide prodrug strategy, we report the discovery of compound <bold>HM-1</bold>Methods In vitro assay of anti-HIV activities in TZM-bl and MT-4 cells, metabolic stability in HLM and human plasma, measurements of water solubility and Log P, assay procedures for hERG activity, acute and subacute toxicity experiment and cytochrome P450 inhibition assay were carried out for <bold>HM-1</bold>.Results <bold>HM-1</bold> can be rapidly hydrolyzed to parent drug <bold>K-5a2</bold> and exhibited high potency against HIV-1_{NL4 − 3} strain (EC₅₀ = 7.99 nM) in TZM-bl cells, HIV-1_IIIB strain (EC₅₀ = 2.9 nM) and HIV-1_Y181C strain (EC₅₀ = 5.5 nM) in MT-4 cells. And it also showed a &gt; 70-fold improvement in aqueous solubility and presented a low acute toxicity in mice (LD₅₀ &gt; 2 g•kg^{− 1}); no obvious organ damage was detected in the assessment of subacute toxicity. Meanwhile, <bold>HM-1</bold> also showed 50 times lower hERG inhibition (IC₅₀ = 6.39 µM) than <bold>K-5a2</bold> (IC₅₀ = 0.13 µM).Conclusions It was <bold>HM-1</bold> appeared to be free of most of the drawbacks associated with <bold>K-5a2</bold> and has been selected for further development as an oral anti-HIV-infection agent.

Aluminum-diamond composites were produced using selective laser melting (SLM) from mechanically mixed diamond and Al12Si powders for use in thermal management applications. The feasibility of SLM for both interface tailoring and simultaneously densification, which are the key for determining the overall thermal conductivity (TC) of the composites, has been investigated. The results indicate that the interface structure of the as-built composites can be controlled, despite the complex physical and chemical nature of SLM. A ‘clean’ diffusion-bonded interface revealed at the micron scale, which is desirable for enhancing TC, was obtained at a laser energy density of 95.2 J/mm3. This demonstrates a possible new potential of SLM in creating metal matrix composites for functional applications. However, despite manipulation of the processing parameters, it was not possible to achieve a relative density above 90%. Thus, how to realize near full density, while maintaining such a ‘clean’ interface during SLM remains a key technical problem for the future. The complex metallurgical mechanisms responsible for interface evolution and microstructure formation are discussed in detail with the aid of finite element analysis, and further densification strategies are proposed.

LD78alpha and LD78beta are 2 highly related nonallelic genes that code for different isoforms of the human CC chemokine macrophage inflammatory protein-1alpha (MIP-1alpha). Two molecular forms of natural LD78beta (7.778 and 7.793 kDa) were identified from conditioned media of stimulated peripheral blood mononuclear cells. Although LD78alpha and LD78beta only differ in 3 amino acids, both LD78beta variants were 100-fold more potent chemoattractants for mouse lymphocytes than was LD78alpha. On the contrary, LD78beta was only 2-fold more efficient than LD78alpha in chemoattracting human lymphocytes and monocytes. Using CC chemokine receptor-transfected cells, both molecular forms of LD78beta proved to be much more potent than LD78alpha in inducing an intracellular calcium rise through CCR5. Compared with LD78alpha and RANTES, this preferential binding of LD78beta to CCR5 resulted in a 10- to 50-fold higher potency in inhibiting infection of peripheral blood mononuclear cells by CCR5-using (R5) HIV-1 strains. To date, LD78beta is the most potent chemokine for inhibiting HIV-1 infection, and can be considered as a potentially important drug candidate for the treatment of infection with R5 HIV-1 strains.

As part of our studies to discover new HIV-1 reverse transcriptase inhibitors, a series of 3,4-dichlorophenyl substituted 1,2,3-thiadiazole thioacetanilide (TTA=[(1,2,3-thiadiazole-5-yl)sulfanyl]acetanilide) derivatives were synthesized, and in vitro anti-HIV activity was evaluated. The results revealed that nearly half of the compounds show moderate-to-good inhibitory potency against HIV-1. In particular, compound 7f is highly potent, with an EC(50) value of 0.95+/-0.33 microM. The preliminary structure-activity relationship among the newly synthesized congeners is discussed.

Early responses of elevated cytokines such as IL-6 reflect the active immune responses, leading to high titers of IgG antibodies against COVID-19.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.