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鉴定可诱导HIV-1转录的苯并唑化合物。

Identification of benzazole compounds that induce HIV-1 transcription.

作者信息

Graci Jason D, Michaels Daniel, Chen Guangming, Schiralli Lester Gillian M, Nodder Sarah, Weetall Marla, Karp Gary M, Gu Zhengxian, Colacino Joseph M, Henderson Andrew J

机构信息

PTC Therapeutics, Inc., South Plainfield, New Jersey, United States of America.

Department of Medicine and Microbiology, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, United States of America.

出版信息

PLoS One. 2017 Jun 28;12(6):e0179100. doi: 10.1371/journal.pone.0179100. eCollection 2017.

DOI:10.1371/journal.pone.0179100
PMID:28658263
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5489165/
Abstract

Despite advances in antiretroviral therapy, HIV-1 infection remains incurable in patients and continues to present a significant public health burden worldwide. While a number of factors contribute to persistent HIV-1 infection in patients, the presence of a stable, long-lived reservoir of latent provirus represents a significant hurdle in realizing an effective cure. One potential strategy to eliminate HIV-1 reservoirs in patients is reactivation of latent provirus with latency reversing agents in combination with antiretroviral therapy, a strategy termed "shock and kill". This strategy has shown limited clinical effectiveness thus far, potentially due to limitations of the few therapeutics currently available. We have identified a novel class of benzazole compounds effective at inducing HIV-1 expression in several cellular models. These compounds do not act via histone deacetylase inhibition or T cell activation, and show specificity in activating HIV-1 in vitro. Initial exploration of structure-activity relationships and pharmaceutical properties indicates that these compounds represent a potential scaffold for development of more potent HIV-1 latency reversing agents.

摘要

尽管抗逆转录病毒疗法取得了进展，但HIV-1感染在患者中仍然无法治愈，并且在全球范围内继续构成重大的公共卫生负担。虽然有许多因素导致患者持续感染HIV-1，但稳定、长寿的潜伏前病毒库的存在是实现有效治愈的一个重大障碍。消除患者体内HIV-1病毒库的一种潜在策略是使用潜伏逆转剂重新激活潜伏前病毒，并联合抗逆转录病毒疗法，这一策略被称为“激活并清除”。到目前为止，这一策略的临床效果有限，可能是由于目前可用的治疗方法较少。我们已经确定了一类新型的苯并唑化合物，它们在几种细胞模型中能够有效诱导HIV-1表达。这些化合物不是通过抑制组蛋白脱乙酰酶或激活T细胞发挥作用，并且在体外激活HIV-1方面具有特异性。对构效关系和药物性质的初步探索表明，这些化合物代表了开发更有效的HIV-1潜伏逆转剂的潜在支架。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/1cee5a9defb4/pone.0179100.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/656fb3bdb3b0/pone.0179100.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/b7c588ef8cde/pone.0179100.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/ba1a4e8da109/pone.0179100.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/52dfc7ecd7dc/pone.0179100.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/72c5ed735711/pone.0179100.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/06d6c501a13c/pone.0179100.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/547f46b0ea7e/pone.0179100.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/1cee5a9defb4/pone.0179100.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/656fb3bdb3b0/pone.0179100.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/b7c588ef8cde/pone.0179100.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/ba1a4e8da109/pone.0179100.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/52dfc7ecd7dc/pone.0179100.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/72c5ed735711/pone.0179100.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/06d6c501a13c/pone.0179100.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/547f46b0ea7e/pone.0179100.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f8e/5489165/1cee5a9defb4/pone.0179100.g008.jpg

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