University of Tennessee Health Sciences Center School of Medicine, Memphis, TN, USA.
University of Queensland Medical School, Brisbane, Queensland, Australia.
J Mol Graph Model. 2023 Nov;124:108539. doi: 10.1016/j.jmgm.2023.108539. Epub 2023 Jun 9.
Kaposi sarcoma (KS) is one of the most common AIDS-related malignant neoplasms, which can leave lesions on the skin among HIV patients. These lesions can be treated with 9-cis-retinoic acid (9-cis-RA), an endogenous ligand of retinoic acid receptors that has been FDA-approved for treatment of KS. However, topical application of 9-cis-RA can induce several unpleasant side effects, like headache, hyperlipidemia, and nausea. Hence, alternative therapeutics with less side effects are desirable. There are case reports associating over-the-counter antihistamine usage with regression of KS. Antihistamines competitively bind to H1 receptor and block the action of histamine, best known for being released in response to allergens. Furthermore, there are already dozens of antihistamines that are FDA-approved with less side effects than 9-cis-RA. This led our team to conduct a series of in-silico assays to determine whether antihistamines can activate retinoic acid receptors. First, we utilized high-throughput virtual screening and molecular dynamics simulations to model high-affinity interactions between antihistamines and retinoic acid receptor beta (RARβ). We then performed systems genetics analysis to identify a genetic association between H1 receptor itself and molecular pathways involved in KS. Together, these findings advocate for exploration of antihistamines against KS, starting with our two promising hit compounds, bepotastine and hydroxyzine, for experimental validation study in the future.
卡波西肉瘤（KS）是最常见的艾滋病相关恶性肿瘤之一，可在 HIV 患者的皮肤中留下病变。这些病变可以用 9-顺式维甲酸（9-cis-RA）治疗，9-cis-RA 是维甲酸受体的内源性配体，已获得 FDA 批准用于治疗 KS。然而，9-cis-RA 的局部应用会引起几种不愉快的副作用，如头痛、高血脂和恶心。因此，需要寻找副作用较小的替代疗法。有病例报告将非处方抗组胺药的使用与 KS 的消退联系起来。抗组胺药竞争性地与 H1 受体结合并阻断组胺的作用，组胺最著名的作用是在对过敏原做出反应时释放。此外，已经有几十种抗组胺药获得了 FDA 的批准，其副作用比 9-cis-RA 少。这促使我们的团队进行了一系列计算机模拟实验，以确定抗组胺药是否可以激活维甲酸受体。首先，我们利用高通量虚拟筛选和分子动力学模拟来模拟抗组胺药与维甲酸受体β（RARβ）之间的高亲和力相互作用。然后，我们进行了系统遗传学分析，以确定 H1 受体本身与涉及 KS 的分子途径之间的遗传关联。这些发现共同提倡探索抗组胺药治疗 KS，首先从我们的两种有前途的命中化合物，贝泊斯汀和羟嗪开始，为未来的实验验证研究。
