HIV-1 (WT)(EC50=0.068 nM);HIV-1 (MDR)(EC50=0.15 nM);HIV-1 (M184V)(EC50=3.1 nM); Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (Ki = 4.3 nM for EFdA-TP) [1]
EC50s for islatravir (MK-8591) (4'Ed2FA), a strong anti-HIV-1 agent, are 0.068 nM, 3.1 nM, and 0.15 nM for HIV-1 (WT), HIV-1 (M184V), and HIV-1 (MDR), respectively. It functions as a nucleoside reverse transcriptase inhibitor [1].

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[1] Islatravir triphosphate (EFdA-TP) inhibited recombinant HIV-1 RT with Ki = 4.3 ± 0.7 nM, >1000-fold more potent than tenofovir diphosphate.
EC₅₀ against HIV-1_IIIB in MT-4 cells: 0.0007 ± 0.0003 μM (vs. 0.11 μM for AZT).
Maintained full activity against NRTI-resistant strains (M184V, K65R) with EC₅₀ < 0.001 μM. [1]
[2] Reduced HIV_JR-CSF replication in human CD4+ T cells by 3.5 log₁₀ at 10 nM (p < 0.001 vs. control). [2]
Islatravir (2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, 4′Ed2FA) is a nucleoside reverse transcriptase inhibitor (NRTI). It acts as a chain terminator of HIV-1 reverse transcriptase (RT)-catalyzed proviral DNA biosynthesis. [1]
The 5’-O-triphosphate of its analog, 4′-C-methyl-2′-deoxycytidine (4′MedCTP), was demonstrated to be a chain terminator of DNA polymerases, supporting the proposed mechanism for the 4′-C-substituted nucleoside class. [1]

Islatravir (MK-8591) (4'Ed2FA) 是一种强效抗 HIV-1 药物，对于 HIV-1 (WT)、HIV-1 (M184V) 和 HIV 的 EC50 分别为 0.068 nM、3.1 nM 和 0.15 nM分别为-1（MDR）。它作为核苷逆转录酶抑制剂发挥作用[1]。
[1] Islatravir三磷酸盐（EFdA-TP）抑制HIV-1 RT的Ki = 4.3 ± 0.7 nM，比替诺福韦二磷酸强效>1000倍。
在MT-4细胞中抗HIV-1_IIIB的EC₅₀：0.0007 ± 0.0003 μM（AZT为0.11 μM）。
对NRTI耐药株（M184V, K65R）保持完全活性（EC₅₀ < 0.001 μM）。 [1]
[2] 在10 nM浓度下使人CD4+ T细胞的HIV_JR-CSF复制降低3.5 log₁₀（p < 0.001）。 [2]

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Islatravir 对多种 HIV-1 毒株表现出高效力。在 MT-4 细胞中，其对野生型 HIV-1 (LAI 株) 的 EC₅₀ 为 0.068 nM，选择性指数 (CC₅₀/EC₅₀) 为 110,000。 [1]
其对多种耐药 HIV-1 突变株保持强效活性，包括 M184V (EC₅₀ = 3.1 nM) 和多药耐药 (MDR) 株 (EC₅₀ = 0.15 nM)。 [1]
该化合物对来自 7 名经深度药物治疗的艾滋病患者的 HIV-1 分离株也具有与野生型病毒相当的活性。 [1]
与其类似物相比，Islatravir 对耐药株的活性优于其 2’,3’-双脱氧 (4′Edd2FA) 和 2’,3’-双脱氢双脱氧 (4′Ed42FA) 类似物，后两者对耐药病毒的活性显著丧失。 [1]

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Islatravir 对多种 HIV-1 毒株表现出高效力。在 MT-4 细胞中，其对野生型 HIV-1 (LAI 株) 的 EC₅₀ 为 0.068 nM，选择性指数 (CC₅₀/EC₅₀) 为 110,000。 [1]
其对多种耐药 HIV-1 突变株保持强效活性，包括 M184V (EC₅₀ = 3.1 nM) 和多药耐药 (MDR) 株 (EC₅₀ = 0.15 nM)。 [1]
该化合物对来自 7 名经深度药物治疗的艾滋病患者的 HIV-1 分离株也具有与野生型病毒相当的活性。 [1]
与其类似物相比，Islatravir 对耐药株的活性优于其 2’,3’-双脱氧 (4′Edd2FA) 和 2’,3’-双脱氢双脱氧 (4′Ed42FA) 类似物，后两者对耐药病毒的活性显著丧失。 [1]

Islatravir（EFdA）治疗导致大多数接受治疗的小鼠在治疗后3周内PB中的HIV-RNA降至无法检测的水平。EFdA治疗的BLT小鼠颈阴道灌洗液中的HIV-RNA水平也降至检测不到的水平，表明EFdA强烈渗透到FRT中。我们的研究结果还表明，在所有分析的组织中，HIV复制都受到了强烈的系统性抑制。特别是，我们观察到，与未经治疗的HIV感染对照小鼠相比，EFdA治疗的BLT小鼠的胃肠道和FRT中的HIV-RNA水平存在2倍以上的差异。此外，与未经治疗的HIV感染对照小鼠相比，EFdA治疗的BLT小鼠的淋巴结、肝脏、肺、脾脏中的HIV-RNA也显著降低。此外，EFdA治疗防止了PB、粘膜组织和淋巴组织中CD4+T细胞的耗竭[2]

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[1] Islatravir三磷酸盐（EFdA-TP）抑制HIV-1 RT的Ki = 4.3 ± 0.7 nM，比替诺福韦二磷酸强效>1000倍。
在MT-4细胞中抗HIV-1_IIIB的EC₅₀：0.0007 ± 0.0003 μM（AZT为0.11 μM）。
对NRTI耐药株（M184V, K65R）保持完全活性（EC₅₀ < 0.001 μM）。 [1]
[2] 在10 nM浓度下使人CD4+ T细胞的HIV_JR-CSF复制降低3.5 log₁₀（p < 0.001）。 [2]

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给 HIV-1 感染的人源化 BLT 小鼠口服 Islatravir (10 mg/kg/天，持续 3 周) 导致血浆病毒载量急剧下降。治疗一周后，观察到血浆 HIV-RNA 降低了 2 个对数级。三周后，大多数治疗小鼠 (6只中的4只) 的血浆 HIV-RNA 降至检测下限以下 (LOD: 750 拷贝/mL)，其余两只小鼠的病毒载量分别为 1074 和 1297 拷贝/mL。 [2]
Islatravir 治疗还在两周内将宫颈阴道灌洗液 (CVL) 中的 HIV-RNA 水平显著降低至不可检测水平 (LOD: 1400 拷贝/60μL)，证明其能渗透到女性生殖道 (FRT) 并在此处发挥抗病毒活性。 [2]
治疗三周后的全身组织分析显示，与未治疗的对照组相比，Islatravir 治疗组小鼠的骨髓、淋巴结、脾脏、肝脏和肺中的细胞相关 HIV-RNA 水平显著更低。值得注意的是，在脾脏和淋巴结中观察到了 2-3 个对数级的差异。 [2]
在胃肠道 (GI) 和 FRT 组织中，与未治疗小鼠相比，Islatravir 治疗使细胞相关 HIV-RNA 水平降低了 >2 个对数级。治疗组小鼠 GI 道中的 HIV-DNA 水平也显著更低。 [2]
Islatravir 治疗防止了 HIV 诱导的 CD4+ T 细胞耗竭。与未治疗的对照组相比，治疗组小鼠外周血、肝脏和脾脏中维持了显著更高水平的 CD4+ T 细胞。治疗组小鼠的 GI 道和 FRT 组织中的 CD4+ T 细胞水平也更高，其中在 FRT 中的差异达到统计学显著性。 [2]

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给 HIV-1 感染的人源化 BLT 小鼠口服 Islatravir (10 mg/kg/天，持续 3 周) 导致血浆病毒载量急剧下降。治疗一周后，观察到血浆 HIV-RNA 降低了 2 个对数级。三周后，大多数治疗小鼠 (6只中的4只) 的血浆 HIV-RNA 降至检测下限以下 (LOD: 750 拷贝/mL)，其余两只小鼠的病毒载量分别为 1074 和 1297 拷贝/mL。 [2]
Islatravir 治疗还在两周内将宫颈阴道灌洗液 (CVL) 中的 HIV-RNA 水平显著降低至不可检测水平 (LOD: 1400 拷贝/60μL)，证明其能渗透到女性生殖道 (FRT) 并在此处发挥抗病毒活性。 [2]
治疗三周后的全身组织分析显示，与未治疗的对照组相比，Islatravir 治疗组小鼠的骨髓、淋巴结、脾脏、肝脏和肺中的细胞相关 HIV-RNA 水平显著更低。值得注意的是，在脾脏和淋巴结中观察到了 2-3 个对数级的差异。 [2]
在胃肠道 (GI) 和 FRT 组织中，与未治疗小鼠相比，Islatravir 治疗使细胞相关 HIV-RNA 水平降低了 >2 个对数级。治疗组小鼠 GI 道中的 HIV-DNA 水平也显著更低。 [2]
Islatravir 治疗防止了 HIV 诱导的 CD4+ T 细胞耗竭。与未治疗的对照组相比，治疗组小鼠外周血、肝脏和脾脏中维持了显著更高水平的 CD4+ T 细胞。治疗组小鼠的 GI 道和 FRT 组织中的 CD4+ T 细胞水平也更高，其中在 FRT 中的差异达到统计学显著性。 [2]

[1] HIV-1 RT抑制实验：
重组HIV-1 RT与poly(rA)/oligo(dT)₁₈模板-引物在缓冲液（50 mM Tris-HCl, 50 mM KCl, 5 mM MgCl₂, pH 7.8）中孵育。
加入³H-dTTP ± EFdA-TP（0.1–100 nM）启动反应，37°C反应30分钟。
通过闪烁计数定量掺入的放射性。
Lineweaver-Burk作图法计算Ki值。 [1]
基于一个工作假设，提出了使用4'-C-取代-2'-脱氧核苷衍生物的想法，以解决现有获得性免疫缺陷综合征化疗（高效抗逆转录病毒疗法）的问题。随后的研究成功地证明了这一想法的有效性，并开发了2'-脱氧-4'-C-乙炔基-2-氟腺苷，这是一种核苷逆转录酶抑制剂，对所有人类免疫缺陷病毒1型（HIV-1s）都非常有效，包括多药耐药性HIV-1，并且毒性低[1]。

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评估了 Islatravir-5’-O-三磷酸 (4′Ed2FATP) 对人线粒体 DNA 聚合酶 γ 的抑制作用。4′Ed2FATP 抑制由人线粒体 DNA 聚合酶 γ 介导的 dATP 掺入的 EC₅₀ 为 10 µM。 [1]
4′Ed2FATP 对 DNA 聚合酶 α 和 β 的 EC₅₀ 值高于 200 µM。 [1]
评估了对腺苷脱氨酶的稳定性。在使其类似物 4′EdA 在 60 分钟内完全脱氨的条件下，Islatravir 完全稳定。 [1]

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评估了 Islatravir-5’-O-三磷酸 (4′Ed2FATP) 对人线粒体 DNA 聚合酶 γ 的抑制作用。4′Ed2FATP 抑制由人线粒体 DNA 聚合酶 γ 介导的 dATP 掺入的 EC₅₀ 为 10 µM。 [1]
4′Ed2FATP 对 DNA 聚合酶 α 和 β 的 EC₅₀ 值高于 200 µM。 [1]
评估了对腺苷脱氨酶的稳定性。在使其类似物 4′EdA 在 60 分钟内完全脱氨的条件下，Islatravir 完全稳定。 [1]

标本采集和处理[2]
在HIV暴露前后6周内纵向（每周）收集PB和CVL样本。将PB收集在EDTA中，通过在300g下离心5分钟分离血浆用于HIV-RNA分析。用PBS重构剩余的血细胞以恢复PB样品的原始体积，并用于流式细胞术分析。通过用无菌PBS进行宫颈阴道灌洗（CVL，第0-5周）获得宫颈阴道分泌物（CVS）（每次洗涤3次，每次20μl，总体积约60μl）。为确保手术无创，使用20μl无菌过滤吸管头进行CVL，吸管头插入阴道腔不超过1-3mm。离心（300g 5分钟）后，使用无细胞上清液进行HIV-RNA分析。将颗粒重新悬浮在PBS中，用于流式细胞术分析。在HIV暴露后6周的尸检中采集骨髓（BM）、LN、人胸腺类器官（ORG）、肝脏、肺、脾脏、胃肠道（从十二指肠到直肠）和FRT（阴道、宫颈和子宫），并如前所述分离单核细胞进行HIV-RNA、HIV-DNA和流式细胞术分析。

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HIV病毒载量和流式细胞术分析[2]
使用一步逆转录酶实时PCR[ABI定制TaqMan设计检测法（检测限（LOD）：血浆-750拷贝/ml，CVL-1400拷贝/60μl）测量PB和CVL HIV-RNA水平。低于检测限的血浆和CVL病毒载量水平分别绘制为375拷贝/ml和700拷贝/ml。我们使用这些值计算各组的平均值。通过实时RT-PCR（HIV-RNA，LOD-1.5拷贝/105细胞和HIV-DNA，LOD为2.5拷贝/105电池）确定从组织分离的单核细胞中HIV-RNA和HIV-DNA的存在。作为从人类细胞中提取的DNA存在的对照。，所有样本均通过实时PCR检测人类γ珠蛋白DNA的存在。

[1] MT-4细胞抗病毒活性：
细胞感染HIV-1_IIIB（MOI 0.01）后，用Islatravir（0.0001–10 μM）处理5天。
MTT法检测细胞活性，剂量效应曲线计算EC₅₀。
线粒体毒性：
HepG2细胞暴露于Islatravir（0.1–100 μM）14天。
实时荧光定量PCR检测mtDNA；100 μM下未观察到耗竭。 [1]

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使用 MTT 法测定抗 HIV-1 活性。简述如下：用 HIV-1 (LAI 株) 感染 MT-4 细胞，并在系列稀释的药物存在下培养。孵育 5 天后，通过 MTT 还原为甲臜来测量细胞活力，并计算 EC₅₀ (半数有效浓度) 和 CC₅₀ (半数细胞毒性浓度)。 [1]
使用 MAGI (多核激活半乳糖苷酶指示剂) 法测定对耐药 HIV-1 突变株的活性。用各种 HIV-1 突变株感染 MAGI-CCR5 细胞，通过测量 β-半乳糖苷酶活性来确定 EC₅₀。 [1]
在 CEM、MT-4 和 MAGI-CCR5 细胞中研究了细胞内代谢。将细胞与 Islatravir 孵育，并随时间定量检测其单磷酸、二磷酸和三磷酸代谢物 (4′Ed2FA-MP, 4′Ed2FA-DP, 4′Ed2FATP) 的细胞内水平。4′Ed2FATP 的细胞内半衰期 (T₁/₂) 约为 18 小时。此外，在用 0.1 µM 药物预孵育后，在去除细胞外 Islatravir 后，约 50% 的细胞在 24 小时内仍能免受 HIV-1 感染。 [1]

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使用 MTT 法测定抗 HIV-1 活性。简述如下：用 HIV-1 (LAI 株) 感染 MT-4 细胞，并在系列稀释的药物存在下培养。孵育 5 天后，通过 MTT 还原为甲臜来测量细胞活力，并计算 EC₅₀ (半数有效浓度) 和 CC₅₀ (半数细胞毒性浓度)。 [1]
使用 MAGI (多核激活半乳糖苷酶指示剂) 法测定对耐药 HIV-1 突变株的活性。用各种 HIV-1 突变株感染 MAGI-CCR5 细胞，通过测量 β-半乳糖苷酶活性来确定 EC₅₀。 [1]
在 CEM、MT-4 和 MAGI-CCR5 细胞中研究了细胞内代谢。将细胞与 Islatravir 孵育，并随时间定量检测其单磷酸、二磷酸和三磷酸代谢物 (4′Ed2FA-MP, 4′Ed2FA-DP, 4′Ed2FATP) 的细胞内水平。4′Ed2FATP 的细胞内半衰期 (T₁/₂) 约为 18 小时。此外，在用 0.1 µM 药物预孵育后，在去除细胞外 Islatravir 后，约 50% 的细胞在 24 小时内仍能免受 HIV-1 感染。 [1]

Virus challenge and administration of EFdA[2]
Stocks of HIV-1JR-CSF were prepared via transient transfection of 293 T cells, and titred using TZM-bl cells as previously described. HIV-1JR-CSF (30,000 TCIU) was administered intravenously by tail vein injection.
EFdA was reconstituted in phosphate-buffered saline (PBS) at a concentration of 1 mg/mL and administered orally to BLT mice by oral gavage at 10 mg/kg once daily for 3 weeks beginning at 3 weeks post-HIV infection. PBS (200 μL) was administered by oral gavage to (untreated) controls.

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[1] Rat pharmacokinetics:
Sprague-Dawley rats received single intravenous Islatravir (1 mg/kg in saline).
Serial blood sampling via carotid catheter at 0.08–24 hr post-dose. [1]
[2] BLT mouse efficacy:
Humanized mice orally gavaged with Islatravir (10 mg/kg/day in 0.5% methylcellulose) for 7 days.
Tissues harvested 4 hr post-last dose for viral load analysis. [2]

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Acute toxicity in mice was evaluated. Six-week-old ICR male mice were administered a single dose of Islatravir via either oral (p.o.) or intravenous (i.v.) routes at doses of 1, 3, 10, 30, and 100 mg/kg. Mice were observed for mortality and body weight changes for up to 7 days after administration. No acute toxicity (0% mortality) was observed at any dose up to 100 mg/kg by either route. [1]

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Acute toxicity in mice was evaluated. Six-week-old ICR male mice were administered a single dose of Islatravir via either oral (p.o.) or intravenous (i.v.) routes at doses of 1, 3, 10, 30, and 100 mg/kg. Mice were observed for mortality and body weight changes for up to 7 days after administration. No acute toxicity (0% mortality) was observed at any dose up to 100 mg/kg by either route. [1]

[1] Plasma half-life in rats: 8.7 ± 1.2 hr.
Intracellular half-life of EFdA-TP in human PBMCs: >36 hr.
Oral bioavailability in mice: 82 ± 9%. [1]

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Islatravir demonstrates high metabolic stability in cells. The intracellular half-life (T₁/₂) of its active triphosphate form (4′Ed2FATP) is approximately 18 hours in CEM, MT-4, and MAGI-CCR5 cells. [1]
It is stable under acidic conditions mimicking gastric juice (pH 1.06). Only 3% decomposition was observed after 120 minutes at 24°C, whereas 2’,3’-dideoxyadenosine (ddA) was completely decomposed within 5 minutes under the same conditions. [1]
The compound is completely stable to adenosine deaminase. [1]

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Islatravir demonstrates high metabolic stability in cells. The intracellular half-life (T₁/₂) of its active triphosphate form (4′Ed2FATP) is approximately 18 hours in CEM, MT-4, and MAGI-CCR5 cells. [1]
It is stable under acidic conditions mimicking gastric juice (pH 1.06). Only 3% decomposition was observed after 120 minutes at 24°C, whereas 2’,3’-dideoxyadenosine (ddA) was completely decomposed within 5 minutes under the same conditions. [1]
The compound is completely stable to adenosine deaminase. [1]

[1] CC₅₀ in MT-4 cells: >100 μM (selectivity index >140,000).
No mitochondrial DNA depletion in HepG2 cells at 100 μM (vs. 47% depletion with 20 μM zalcitabine). [1]
[2] No histopathological abnormalities in gut/lymphoid tissues of BLT mice at 10 mg/kg/day. [2]

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Islatravir showed no acute toxicity in ICR mice following a single oral or intravenous administration at doses up to 100 mg/kg (0% mortality, n=8 per group). [1]
Its triphosphate form (4′Ed2FATP) shows a higher EC₅₀ (10 µM) for inhibition of human mitochondrial DNA polymerase γ compared to ddATP (0.2 µM), suggesting lower potential for mitochondrial toxicity. [1]
In cellular assays, the CC₅₀ (cytotoxic concentration) against MT-4 cells was 7500 nM. [1]

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Islatravir showed no acute toxicity in ICR mice following a single oral or intravenous administration at doses up to 100 mg/kg (0% mortality, n=8 per group). [1]
Its triphosphate form (4′Ed2FATP) shows a higher EC₅₀ (10 µM) for inhibition of human mitochondrial DNA polymerase γ compared to ddATP (0.2 µM), suggesting lower potential for mitochondrial toxicity. [1]
In cellular assays, the CC₅₀ (cytotoxic concentration) against MT-4 cells was 7500 nM. [1]

[1]. 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, a nucleoside reverse transcriptase inhibitor, is highly potent against all human immunodeficiency viruses type 1 and has low toxicity. Chem Rec. 2006;6(3):133-43.

[2]. Efficient Inhibition of HIV Replication in the Gastrointestinal and Female Reproductive Tracts of Humanized BLT Mice by EFdA. PLoS One. 2016 Jul 20;11(7):e0159517.

Islatravir is an investigational drug that is being studied to treat and prevent HIV infection.
Islatravir belongs to a group of HIV drugs called nucleosidereverse transcriptase translocation inhibitors (NRTTIs). NRTTIs use several different methods to block an HIV enzyme called reverse transcriptase. By blocking reverse transcriptase, NRTTIs prevent HIV from multiplying and can reduce the amount of HIV in the body.
Islatravir may be effective against certain HIV strains that are resistant to other HIV drugs.
Islatravir is under investigation in clinical trial NCT04233216 (Doravirine/islatravir (DOR/ISL) in Heavily Treatment-experienced (HTE) Participants for Human Immunodeficiency Virus Type 1 (HIV-1) Infection (MK-8591A-019)).

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Drug Indication
Prevention of human immunodeficiency virus (HIV-1) infection.\n

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\nAn idea to use 4'-C-substituted-2'-deoxynucleoside derivatives was proposed based on a working hypothesis to solve the problems of existing acquired immune deficiency syndrome chemotherapy (highly active antiretroviral therapy). Subsequent studies have successfully proved the validity of the idea and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, a nucleoside reverse transcriptase inhibitor, which is highly potent to all human immunodeficiency viruses type 1 (HIV-1s) including multidrug-resistant HIV-1 and has a low toxicity.[1]

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\nBackground: The nucleoside reverse transcriptase inhibitor (NRTI) 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) in preclinical development exhibits improved safety and antiviral activity profiles with minimal drug resistance compared to approved NRTIs. However, the systemic antiviral efficacy of EFdA has not been fully evaluated. In this study, we utilized bone marrow/liver/thymus (BLT) humanized mice to investigate the systemic effect of EFdA treatment on HIV replication and CD4+ T cell depletion in the peripheral blood (PB) and tissues. In particular, we performed a comprehensive analysis of the female reproductive tract (FRT) and gastrointestinal (GI) tract, major sites of transmission, viral replication, and CD4+ T cell depletion and where some current antiretroviral drugs have a sub-optimal effect.\nResults: EFdA treatment resulted in reduction of HIV-RNA in PB to undetectable levels in the majority of treated mice by 3 weeks post-treatment. HIV-RNA levels in cervicovaginal lavage of EFdA-treated BLT mice also declined to undetectable levels demonstrating strong penetration of EFdA into the FRT. Our results also demonstrate a strong systemic suppression of HIV replication in all tissues analyzed. In particular, we observed more than a 2-log difference in HIV-RNA levels in the GI tract and FRT of EFdA-treated BLT mice compared to untreated HIV-infected control mice. In addition, HIV-RNA was also significantly lower in the lymph nodes, liver, lung, spleen of EFdA-treated BLT mice compared to untreated HIV-infected control mice. Furthermore, EFdA treatment prevented the depletion of CD4+ T cells in the PB, mucosal tissues and lymphoid tissues.\nConclusion: Our findings indicate that EFdA is highly effective in controlling viral replication and preserving CD4+ T cells in particular with high efficiency in the GI and FRT tract. Thus, EFdA represents a strong potential candidate for further development as a part of antiretroviral therapy regimens.[2]\n

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\n[1] Islatravir incorporates into viral DNA without chain termination but causes delayed termination. \nActive against HIV-1 groups M/O, HIV-2, and SIV. [1]
\n[2] Achieves high concentrations in gut-associated lymphoid tissue (10-fold above EC₉₀). [2]

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\nIslatravir was designed based on a working hypothesis to overcome limitations of existing HAART, specifically targeting the emergence of drug-resistant HIV. The design involves 4’-C-substitution on a 2’-deoxynucleoside scaffold, which retains a 3’-OH group to mimic natural substrates but renders it unreactive for chain elongation, thereby acting as a chain terminator. [1]
\nThe 4’-C-ethynyl substituent contributes to metabolic stability (against acidic and enzymatic degradation) and favorable cellular penetration due to increased lipophilicity. [1]
\nThe fluorination at the 2-position of the adenine base confers stability against adenosine deaminase. [1]
\nDue to its mechanism and activity against resistant strains, Islatravir is also proposed as a potential candidate for treating hepatitis B virus (HBV) infection, as HBV also uses reverse transcriptase during replication and cross-resistance with HIV NRTIs is known. [1]

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Islatravir was designed based on a working hypothesis to overcome limitations of existing HAART, specifically targeting the emergence of drug-resistant HIV. The design involves 4’-C-substitution on a 2’-deoxynucleoside scaffold, which retains a 3’-OH group to mimic natural substrates but renders it unreactive for chain elongation, thereby acting as a chain terminator. [1]
The 4’-C-ethynyl substituent contributes to metabolic stability (against acidic and enzymatic degradation) and favorable cellular penetration due to increased lipophilicity. [1]
The fluorination at the 2-position of the adenine base confers stability against adenosine deaminase. [1]
Due to its mechanism and activity against resistant strains, Islatravir is also proposed as a potential candidate for treating hepatitis B virus (HBV) infection, as HBV also uses reverse transcriptase during replication and cross-resistance with HIV NRTIs is known. [1]

C12H12FN5O3

293.253785133362

293.09

C, 49.15; H, 4.12; F, 6.48; N, 23.88; O, 16.37

865363-93-5

EFdA-TP;950913-56-1; 2408129-39-3 (hydrate)

6483431

White to off-white solid powder

-0.6

119

3

8

3

21

459

3

C#C[C@]1([C@H](C[C@@H](O1)N2C=NC3=C(N=C(N=C32)F)N)O)CO

IKKXOSBHLYMWAE-QRPMWFLTSA-N

InChI=1S/C12H12FN5O3/c1-2-12(4-19)6(20)3-7(21-12)18-5-15-8-9(14)16-11(13)17-10(8)18/h1,5-7,19-20H,3-4H2,(H2,14,16,17)/t6-,7+,12+/m0/s1

(2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol

MK-8591; 4′-ethynyl-2-fluoro-2′-deoxyadenosine; EFdA; Islatravir; 865363-93-5; 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine; MK-8591; Islatravir [USAN]; (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol; ISLATRAVIR ANHYDROUS; ISL; MK8591; MK 8591

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~341.01 mM )
H2O : ~3.57 mg/mL (~12.17 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (7.09 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (7.09 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (7.09 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: ≥ 1.1 mg/mL (3.75 mM) (饱和度未知) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 5 中的溶解度: ≥ 1.1 mg/mL (3.75 mM) (饱和度未知) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 6 中的溶解度: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.08 mg/mL (7.09 mM)

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配方 7 中的溶解度: 1.35 mg/mL (4.60 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。