Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro.
Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro.
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苔藓抑素是一个独特的领导在发展潜在的变革性疗法的癌症，阿尔茨海默病，和根除艾滋病毒/艾滋病。然而，苔藓抑素的临床使用受到其有限供应、难以获得临床相关衍生物和副作用的阻碍。在这里，我们解决这些问题，通过一个新的家庭设计苔藓抑素类似物的七个成员的步骤经济的合成利用高度收敛的普林斯大环化策略。我们还首次证明了这种类似物在体外有效地诱导潜伏的HIV活化，其效力类似于或优于苔藓抑素。值得注意的是，这些类似物在诱导潜伏性HIV表达方面比prostratin（目前用于潜伏性病毒诱导的临床候选物）更有效达1000倍。这项研究首次证明，设计的，合成可获得的苔藓抑素类似物可以作为上级候选人，通过诱导潜伏的病毒库与目前的抗逆转录病毒治疗相结合，用于根除艾滋病毒/艾滋病。
Bryostatin is a unique lead in the development of potentially transformative therapies for cancer, Alzheimer’s disease, and the eradication of HIV/AIDS. However, the clinical use of bryostatin has been hampered by its limited supply, difficulties in accessing clinically-relevant derivatives, and side effects. Herein, we address these problems through the step-economical syntheses of seven members of a new family of designed bryostatin analogues utilizing a highly convergent Prins-macrocyclization strategy. We also demonstrate for the first time that such analogues effectively induce latent HIV activation in vitro with potencies similar to or better than bryostatin. Significantly, these analogues are up to 1000-fold more potent in inducing latent HIV expression than prostratin, the current clinical candidate for latent virus induction. This study provides the first demonstration that designed, synthetically-accessible bryostatin analogues could serve as superior candidates for the eradication of HIV/AIDS through induction of latent viral reservoirs in conjunction with current antiretroviral therapy.
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