A series of diaryltriazines and diarylpyrimidines are highly potent nonnucleoside reverse transcriptase inhibitors with possible applications as microbicides
A series of diaryltriazines and diarylpyrimidines are highly potent nonnucleoside reverse transcriptase inhibitors with possible applications as microbicides
复制标题
DOI：
10.1128/aac.48.10.3684-3689.2004
复制
发表时间：
2004-10-01
影响因子：
4.9
通讯作者：
Lewi, P
中科院分区：
文献类型：
--
作者：
Van Herrewege, Y;Vanham, G;Lewi, P
单核细胞衍生的树突状细胞（MO-DC）和CD 4（+）T细胞（代表性人类免疫缺陷病毒（HIV）传播的主要靶点）的体外模型用于评价新型非核苷逆转录酶抑制剂二芳基三嗪（DATA）和二芳基嘧啶（DAPY）与参比化合物UC-781和PMPA相比的抗病毒和免疫抑制活性。通过在14天期间用一定剂量范围的化合物处理HIV感染的MO-DC/CD 4（+）-T细胞共培养物，然后在HIV p24抗原酶联免疫吸附测定中分析上清液，测定抗病毒活性（通过50%有效浓度[EC 50]反映）。一个有限的，24小时的治疗评价的化合物作为杀微生物剂。在PCR中通过监测具有植物血凝素-白细胞介素-2母细胞的次级培养物中的前病毒DNA来评价病毒拯救。我们在MO-DC和同种异体T细胞的混合白细胞培养物中测定了50%的免疫抑制浓度，其中化合物连续存在或仅在前24小时内存在。DATA和DAPY化合物的EC 50值范围为0.05至3 nM，而UC-781为50 nM，PMPA为89 nM。当在“杀微生物剂”环境中进行评估时，最有效的化合物在10至100 nM时完全阻断HIV感染。免疫抑制浓度远高于EC 50，导致所有测试化合物的有利治疗指数。这里描述的DATA和DAPY化合物比早期的逆转录酶抑制剂更有效，并且在体外显示出有利的药理学特征。它们可以加强抗逆转录病毒药物，并可能用作杀微生物剂。
An in vitro model of monocyte-derived dendritic cells (MO-DC) and CD4(+) T cells, representing the primary targets of sexual human immunodeficiency virus (HIV) transmission, was used to evaluate the antiviral and immune suppressive activity of new classes of nonnucleoside reverse transcriptase inhibitors, diaryltriazines (DATAs) and diarylpyrimidines (DAPYs), compared to the reference compounds UC-781 and PMPA. Antiviral activity (as reflected by the 50% effective concentration [EC50]) was determined by treating HIV-infected MO-DC/CD4(+)-T-cell cocultures with a dose range of a compound during 14 days, followed by analysis of supernatants in HIV p24 antigen enzyme-linked immunosorbent assay. A limited, 24-h treatment evaluated the compounds as microbicides. Viral rescue was evaluated in a PCR by monitoring proviral DNA in secondary cultures with phytohemagglutinin-interieukin-2 blasts. We determined 50% immunosuppressive concentrations in mixed leukocyte cultures of MO-DC and allogeneic T cells, with compound either continuously present or present only during the first 24 h. The EC50 values of DATA and DAPY compounds ranged from 0.05 to 3 nM compared to 50 nM for UC-781 and 89 nM for PMPA. When evaluated in the "microbicide" setting, the most potent compounds completely blocked HIV infection at 10 to 100 nM. The immunosuppressive concentrations were well above the EC50, resulting in favorable therapeutic indices for all compounds tested. The DATA and DAPY compounds described here are more potent than earlier reverse transcriptase inhibitors and show favorable pharmacological profiles in vitro. They could strengthen the antiretroviral armamentarium and might be useful as microbicides.