The entry inhibitor DS003 (BMS-599793): a BMS-806 analogue, provides superior activity as a pre-exposure prophylaxis candidate.
The entry inhibitor DS003 (BMS-599793): a BMS-806 analogue, provides superior activity as a pre-exposure prophylaxis candidate.
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DOI：
10.1097/qad.0000000000002974
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发表时间：
2021-10-01
期刊：
影响因子：
--
通讯作者：
Shattock RJ
中科院分区：
文献类型：
--
作者：
Herrera C;Harman S;Aldon Y;Rogers P;Armanasco N;Ziprin P;Stieh D;Nuttall J;Shattock RJ
能够结合gp 120并阻止CD 4诱导的HIV-1包膜构象变化的小分子抑制剂提供了一类重要的抑制剂。目前，只有Fostemsavir被批准用于HAART，这使得这类抑制剂成为预防的有吸引力的候选药物。我们评估了DS 003（BMS-599793）（BMS-378806的类似物）在不同粘膜组织中的活性，并阐明了其作用机制。使用人粘膜组织模型作为体内活性的替代物进行临床前分析。在粘膜组织外植体（宫颈外、阴茎和结直肠）和跨感染模型（树突状细胞或粘膜迁移细胞与CD 4 +T细胞的共培养物）中评估了DS 003在多次给药（2 h、24 h和持续给药）和与融合抑制剂联合给药时的抗病毒疗效。通过流式细胞术和生物层干涉测量法评估了DS 003与gp 120的结合，并在竞争性研究中使用可溶性CD 4（sCD 4）和抗CD 4诱导抗体17 b进一步探测。在所有模型中，DS 003的抑制活性随着暴露时间的延长以及与融合抑制剂联合使用而增加。预先暴露于sCD 4阻碍了DS 003与病毒包膜（Env）的结合。相比之下，DS 003不影响sCD 4的后续结合。此外，在存在DS 003的情况下，通过17 b结合评估的sCD 4诱导的表位暴露显著降低。DS 003通过结合至gp 120的CD 4结合位点或其附近抑制HIV-1感染，阻止CD 4诱导的病毒融合所必需的构象变化。这些数据强调了DS 003作为暴露前预防候选药物的开发潜力。
Small molecule inhibitors able to bind to gp120 and prevent CD4-induced HIV-1 envelope conformational change provide an important class of inhibitors. Currently, only Fostemsavir is approved for HAART, which makes this class of inhibitors attractive candidates for prevention. We assessed the activity of DS003 (BMS-599793), an analogue of BMS-378806, in different mucosal tissues and elucidated its mechanism of action. Pre-clinical analysis was performed with human mucosal tissue models as surrogates of in vivo activity. Antiviral efficacy of DS003 was assessed in mucosal tissue explants (ecto-cervical, penile and colorectal) and in trans-infection models (co-cultures of dendritic or mucosal migratory cells with CD4+T cells) with several dosing times (2 h, 24 h and sustained) and in combination with a fusion inhibitor. Binding of DS003 to gp120 was assessed by flow cytometry and bio-layer interferometry and further probed in competitive studies using soluble CD4 (sCD4) and an anti-CD4 induced antibody, 17b. In all models, the inhibitory activity of DS003 was increased with longer periods of exposure and by combination with a fusion inhibitor. Pre-exposure to sCD4 impeded DS003 binding to viral envelope (Env). In contrast, DS003 did not impact subsequent binding of sCD4. Furthermore, sCD4-induced epitope exposure as assessed by 17b binding was significantly reduced in the presence of DS003. DS003 inhibits HIV-1 infection by binding to or near the CD4 binding site of gp120, preventing CD4-induced conformational change essential for viral fusion. These data highlight the potential of DS003 for development as a pre-exposure prophylaxis candidate.
影响因子：
6.7
作者：
Dereuddre-Bosquet N;Morellato-Castillo L;Brouwers J;Augustijns P;Bouchemal K;Ponchel G;Ramos OH;Herrera C;Stefanidou M;Shattock R;Heyndrickx L;Vanham G;Kessler P;Le Grand R;Martin L
通讯作者：
Martin L