據(jù)美國每日科學(xué)網(wǎng)9月26日報道，美國猶他州大學(xué)研究人員開發(fā)出一種新型殺菌素,，能和艾滋病（HIV）病毒包膜上的糖結(jié)合,，從而阻止其繼續(xù)感染,。該成果有望作為一種新的早期療法，預(yù)防HIV通過性途徑傳播,。該研究發(fā)表在近期的在線雜志《分子制藥》上,。
多年來，殺菌素多是凝膠形式來預(yù)防HIV通過性途徑傳播,，但收效甚微,。HIV要形成感染,，必須首先進(jìn)入宿主細(xì)胞，然后控制細(xì)胞復(fù)制機(jī)制來自我復(fù)制,，新的HIV再去感染其它細(xì)胞。在病毒進(jìn)入與復(fù)制這兩步中,，都為抗艾滋病藥物提供了潛在靶點(diǎn),。論文作者、猶他州大學(xué)生物工程與制藥化學(xué)副教授帕德里克·基瑟說：“但目前臨床試驗中所用的抗HIV藥物,，大部分都是瞄準(zhǔn)病毒的復(fù)制系統(tǒng),；而在阻止病毒進(jìn)入方面研究很少，這種方法能在病毒和目標(biāo)細(xì)胞作用之前就使其失去活性，同時,，這種方法成本很高且產(chǎn)量極低,。外源凝集素（Lectins）就是這種方法中使用的藥物。”
外源凝集素是自然界發(fā)現(xiàn)的一類分子,，能和某些特殊的糖結(jié)合在一起,。HIV病毒外面包著一層糖類包膜，能使它們躲過免疫系統(tǒng),。此前的研究顯示,，從植物和細(xì)菌中提取的外源凝集素能和HIV包膜上的糖結(jié)合，從而阻止其進(jìn)入細(xì)胞,。
但生產(chǎn)和提純天然外源凝集素成本高得嚇人,。而基瑟和同事在一種名為（BzB）的化合物的基礎(chǔ)上，開發(fā)出了一種人工合成的外源凝集素,，能和HIV上面的糖殘基結(jié)合,，并加強(qiáng)了二者間的結(jié)合鍵，開發(fā)出了合成外源凝集素多聚物,，由相同的亞單元構(gòu)成,，每個亞單元都包含了多重BzB結(jié)合位點(diǎn)。增加了BzB結(jié)合位點(diǎn)的數(shù)量和密度后,，聚合物能更好地與HIV結(jié)合,，大大提高了其抗病毒能力。
由于HIV變種很多,，其病毒包膜上的糖也大不相同,，基瑟和同事還對合成外源凝集素的光譜抗病毒性進(jìn)行了評價，發(fā)現(xiàn)其不僅對廣泛的HIV病毒種顯出了同樣的抵抗力,，而且還是專門針對HIV的,，對其它病毒的包膜沒有影響。此外,，他們還評價了該聚合物在一種果糖（精液中的糖,，能中和外源凝集素類藥物效力）中的抗HIV能力，發(fā)現(xiàn)其抗病毒能力在果糖中完全無損,。
“這種多聚物在抗NIV方面非常有效,，將一塊方糖大小的BzB多聚物溶化在一浴缸的水中，其濃度足以阻止HIV感染細(xì)胞,。”基瑟說,，“理想的抗HIV殺菌素包括效能、廣譜性,、選擇抑制性,、生物產(chǎn)量以及生物適應(yīng)性等多方面,。這些以BzB為基礎(chǔ)的合成外源凝集素好像符合了所有這些關(guān)鍵的指標(biāo)，為那些HIV流行的地區(qū),，提供了一種可負(fù)擔(dān)得起的,，還具有升級潛力的干預(yù)式性傳播預(yù)防藥物”。
基瑟還表示,，今后的研究將集中在對這些合成外源凝集素的效能評價上,，觀察它們被人體吸收后，預(yù)防HIV在組織間傳播的效果,，還將在靈長類動物身上進(jìn)行測試,。目前他們正在開發(fā)一種凝膠形式的聚合物，可預(yù)防HIV通過性途徑傳播,。(生物谷 Bioon.com)
doi:10.1021/mp2002957
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Activity and Safety of Synthetic Lectins Based on Benzoboroxole-Functionalized Polymers for Inhibition of HIV Entry
Alamelu Mahalingam, Anthony R. Geonnotti, Jan Balzarini, and Patrick F. Kiser
Lectins derived from plant and microbial sources constitute a vital class of entry inhibitors that target the oligomannose residues on the HIV envelope gp120. Despite their potency and specificity, success of lectin-based entry inhibitors may be impeded by high manufacturing costs, formulation and potential mitogenicity. Therefore, there exists a gap in the HIV microbicides pipeline that underscores the need for mass producible, synthetic, broad-spectrum, and biocomptabile inhibitors of HIV entry. Here, we present the development of a polymeric synthetic lectin, based on benzoboroxole (BzB), which exhibits weak affinity (25 M–1) for nonreducing sugars, similar to those found on the HIV envelope. High molecular weight BzB-functionalized polymers demonstrated antiviral activity that increased with an increase in ligand density and molecular weight of the polymer construct, revealing that polyvalency improves activity. Polymers showed significant increase in activity from 25 to 75 mol % BzB functionalization with EC50 of 15 μM and 15 nM, respectively. A further increase in mole functionalization to 90% resulted in an increase of the EC50 (59 ± 5 nM). An increase in molecular weight of the polymer at 50 mol % BzB functionalization showed a gradual but significant increase in antiviral activity, with the highest activity seen with the 382 kDa polymer (EC50 of 1.1 ± 0.5 nM in CEM cells and 11 ± 3 nM in TZM-bl cells). Supplementing the polymer backbone with 10 mol % sulfonic acid not only increased the aqueous solubility of the polymers by at least 50-fold but also demonstrated a synergistic increase in anti-HIV activity (4.0 ± 1.5 nM in TZM-bl cells), possibly due to electrostatic interactions between the negatively charged polymer backbone and the positively charged V3-loop in the gp120. The benzoboroxole-sulfonic acid copolymers showed no decrease in activity in the presence of a seminal concentration of fructose (p > 0.05). Additionally, the copolymers exhibit minimal, if any, effect on the cellular viability, barrier properties, or cytokine levels in human reconstructed ectocervical tissue after 3 days of repeated exposure and did not show pronounced activity against a variety of other RNA and DNA viruses.
