Comparative Pharmacokinetics of a Dual Inhibitor of HIV-1, NBD-14189, in Rats and Dogs with a Proof-of-Concept Evaluation of Antiviral Potency in SCID-hu Mouse Model.
Comparative Pharmacokinetics of a Dual Inhibitor of HIV-1, NBD-14189, in Rats and Dogs with a Proof-of-Concept Evaluation of Antiviral Potency in SCID-hu Mouse Model.
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DOI：
10.3390/v14102268
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发表时间：
2022-10-16
期刊：
影响因子：
--
通讯作者：
Debnath AK
中科院分区：
文献类型：
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作者：
Stoddart CA;Curreli F;Horrigan S;Altieri A;Kurkin AV;Debnath AK
我们之前报道了gp120拮抗剂的设计取得了实质性进展。值得注意的是，我们发现NBD-14189不仅是最活跃的gp120拮抗剂，而且对HIV-1逆转录酶（RT）具有抗病毒活性。我们还通过x射线晶体学证实了它与HIV-1 RT的结合。这种双重抑制是非常重要的，因为有趣的是，这种化合物连接了dNTP和nnrti结合位点，并在酶分析中抑制了分离RT的聚合酶活性。这一新发现有望为设计新型HIV-1双重抑制剂开辟新的途径。因此，我们需要将这种抑制剂推进到临床前评估。为此，我们报道了NBD-14189在大鼠和狗体内的药代动力学（PK）研究。随后，我们在SCID-hu Thy/Liv小鼠模型中评估了其体内毒性和治疗效果。PK数据显示其具有良好的半衰期（t1/2）和良好的口服生物利用度（%F = 61%）。NBD-14189在小鼠中没有显示出任何可测量的毒性，并且在没有明确证据表明对HIV介导的人类胸腺细胞耗损有保护作用的情况下，每天300 mg/kg的治疗减少了HIV复制。这些数据表明这种抑制剂作为抗hiv -1药物的潜力，需要在非人灵长类动物（NHP）模型中进行评估。
We earlier reported substantial progress in designing gp120 antagonists. Notably, we discovered that NBD-14189 is not only the most active gp120 antagonist but also shows antiviral activity against HIV-1 Reverse Transcriptase (RT). We also confirmed its binding to HIV-1 RT by X-ray crystallography. The dual inhibition is highly significant because, intriguingly, this compound bridges the dNTP and NNRTI-binding sites and inhibits the polymerase activity of isolated RT in the enzymatic assay. This novel finding is expected to lead to new avenues in designing a novel class of HIV-1 dual inhibitors. Therefore, we needed to advance this inhibitor to preclinical assessment. To this end, we report the pharmacokinetics (PK) study of NBD-14189 in rats and dogs. Subsequently, we assessed the toxicity and therapeutic efficacy in vivo in the SCID-hu Thy/Liv mouse model. The PK data indicated a favorable half-life (t1/2) and excellent oral bioavailability (%F = 61%). NBD-14189 did not show any measurable toxicity in the mice, and treatment reduced HIV replication at 300 mg/kg per day in the absence of clear evidence of protection from HIV-mediated human thymocyte depletion. The data indicated the potential of this inhibitor as an anti-HIV-1 agent and needs to be assessed in a non-human primate (NHP) model.
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影响因子：
3.7
作者：
Stoddart CA;Bales CA;Bare JC;Chkhenkeli G;Galkina SA;Kinkade AN;Moreno ME;Rivera JM;Ronquillo RE;Sloan B;Black PL
通讯作者：
Black PL
影响因子：
7.3
作者：
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通讯作者：
Debnath, Asim K.
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通讯作者：
McCune, JM
影响因子：
16.1
作者：
Lataillade, Max;Lalezari, Jacob P.;Llamoso, Cyril
通讯作者：
Llamoso, Cyril
影响因子：
21.8
作者：
通讯作者：
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