Bevirimat
(Synonyms: 贝韦立马; PA-457; MPC-4326; YK FH312) 目录号 : GC35508
An inhibitor of HIV-1 virion maturation
Cas No.:174022-42-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
PA-457 is an inhibitor of HIV-1 virion maturation.1,2 It inhibits the cleavage of the Gag capsid (CA) precursor CA-SP1 to the mature CA protein. PA-457 inhibits the replication of drug-sensitive and -resistant clinical isolates of HIV-1 in isolated human peripheral blood mononuclear cells (PBMCs; mean IC50s = 10.3 and 7.8 nM, respectively).3 In vivo, it prevents replication of HIV-1 in SCID-hu Thy/Liv mice when administered at a dose of 100 mg/kg.4
1.Martin, D.E., Salzwedel, K., and Allaway, G.P.Bevirimat: A novel maturation inhibitor for the treatment of HIV-1 infectionAntivir. Chem. Chemother.19(3)107-113(2008) 2.Wang, D., Lu, W., and Li, F.Pharmacological intervention of HIV-1 maturationActa Phatm. Sin. B5(6)493-499(2015) 3.Li, F., Goila-Gaur, R., Salzwedel, K., et al.PA-457: A potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processingProc. Natl. Acad. Sci. USA100(23)13555-13560(2003) 4.Soddart, C.A., Joshi, P., Sloan, B., et al.Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv micePLoS One2(11)e1251(2007)
| Cas No. | 174022-42-5 | SDF | |
| 别名 | 贝韦立马; PA-457; MPC-4326; YK FH312 | ||
| Canonical SMILES | OC([C@]1(CC[C@H]2C(C)=C)[C@@]2([H])[C@](CC[C@@]3([H])[C@]4(CC[C@]5([H])[C@@]3(CC[C@H](OC(CC(C)(C)C(O)=O)=O)C5(C)C)C)C)([H])[C@@]4(C)CC1)=O | ||
| 分子式 | C36H56O6 | 分子量 | 584.83 |
| 溶解度 | DMSO: ≥ 50 mg/mL (85.49 mM); Water: < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7099 mL | 8.5495 mL | 17.099 mL |
| 5 mM | 0.342 mL | 1.7099 mL | 3.4198 mL |
| 10 mM | 0.171 mL | 0.8549 mL | 1.7099 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Bevirimat: a novel maturation inhibitor for the treatment of HIV-1 infection
Antivir Chem Chemother 2008;19(3):107-13.PMID:19024627DOI:10.1177/095632020801900301.
Existing antiretroviral treatments for HIV type-1 (HIV-1) disease are limited by problems of resistance and drug-drug interactions. Bevirimat is a novel HIV-1 maturation inhibitor with a mechanism of action that is distinct from other antiretroviral agents. Specific inhibition of the final rate-limiting step in Gag processing by Bevirimat prevents release of mature capsid protein from its precursor (CA-SP1), resulting in the production of immature, non-infectious virus particles. Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer Bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients, with peak plasma concentrations attained approximately 1-3 h after dosing. Plasma concentrations decrease in a log-linear manner with a mean plasma elimination halflife of 58-80 h, supporting once-daily dosing. Animal studies suggest that elimination of Bevirimat is primarily by hepatic glucuronidation and hepatobiliary excretion. There is minimal renal elimination, with < 1% of the administered dose appearing in the urine. In responsive patients, Bevirimat has demonstrated a robust dosedependent reduction in viral load (> 1.5 log10 copies/ml). Short-term administration (< or = 14 days) of Bevirimat is well tolerated, even when used in combination with other antiretroviral agents. Further studies to evaluate the long-term efficacy and tolerability of Bevirimat are currently underway.
Multiple-dose pharmacokinetics and safety of Bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers
Clin Pharmacokinet 2007;46(7):589-98.PMID:17596104DOI:10.2165/00003088-200746070-00004.
Background and objective: Bevirimat [3-O-(3',3'-dimethylsuccinyl)-betulinic acid] is a novel inhibitor of HIV-1 maturation. This study was performed to investigate the pharmacokinetics and safety of Bevirimat during repeated dosing in healthy volunteers. Subjects and methods: The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study. A total of 48 healthy male volunteers, aged 19-54 years, took part in the study. Treatment was administered for 10 days in six escalating dose cohorts (n = 8 in each cohort; 6 Bevirimat, 2 placebo). The doses of Bevirimat given in each successive cohort were 25 mg, 50 mg, 75 mg (with 150 mg loading dose), 100 mg, 150 mg and 200mg. Safety follow-up was performed 28 days after the first dose. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Plasma Bevirimat levels were measured from blood samples collected pre-dose on days 1-10 and then at approximately 48-hour intervals until 21 days after dosing started. On days 1 and 10, further blood samples were obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours after dosing. Urine samples were collected in the morning on days 1, 5 and 11 and at the end of the study for the measurement of cortisol and 6beta-hydroxycortisol. The pharmacokinetic parameters of Bevirimat were estimated using non-compartmental methods. Main outcome measure: Dose proportionality of exposure to Bevirimat, assessed by the maximum plasma concentration and the area under the plasma concentration-time curve. Results: The mean terminal elimination half-life of Bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour. Bevirimat showed approximately 4-fold greater accumulation on day 10 compared with day 1, and the degree of accumulation was similar with all doses. Maximum plasma concentrations ranged from 8 to 58 microg/mL at day 10. Testing for dose-proportionality showed that exposure to Bevirimat was proportional to the dose, both after a single dose and after repeat dosing for 10 days. Measurement of the urinary 6beta-hydroxycortisol/cortisol ratio indicated that Bevirimat did not affect cytochrome P450 3A activity. Repeated dosing with Bevirimat for 10 days was well tolerated. There was no increase in adverse events observed for Bevirimat compared with placebo, and no serious adverse events occurred. No clinically relevant changes in vital signs, physical examination or clinical laboratory evaluations were observed. Conclusions: Bevirimat shows dose-proportional pharmacokinetics during repeated dosing for 10 days. Its accumulation is approximately 4-fold greater on day 10 compared with day 1. Repeated dosing with Bevirimat is well tolerated. These properties make Bevirimat potentially suitable for inclusion in highly active antiretroviral therapy regimens.
High prevalence of Bevirimat resistance mutations in protease inhibitor-resistant HIV isolates
AIDS 2010 Mar 13;24(5):669-73.PMID:19926962DOI:10.1097/QAD.0b013e32833160fa.
Objective: Bevirimat is the first drug of a new class of antivirals that hamper the maturation of HIV. The objective of this study was to evaluate the sequence variability of the gag region targeted by Bevirimat in HIV subtype-B isolates. Methods: Of 484 HIV subtype-B isolates, the gag region comprising amino acids 357-382 was sequenced. Of the patients included, 270 were treatment naive and 214 were treatment experienced. In the latter group, 48 HIV isolates harboured mutations associated with reverse transcriptase inhibitor resistance only, and 166 HIV isolates carried mutations associated with protease inhibitor resistance. Results: In the treatment-naive patient population, approximately 30% harboured an HIV isolate with at least one mutation associated with a reduced susceptibility to Bevirimat (H358Y, L363M, Q369H, V370A/M/del and T371del). In HIV isolates with protease inhibitor resistance, the prevalence of Bevirimat resistance mutations increased to 45%. Accumulation of mutations at four positions in the Bevirimat target region, S368C, Q369H, V370A and S373P, was significantly observed. Mutations associated with Bevirimat resistance were detected more frequently in HIV isolates with three or more protease inhibitor resistance mutations than in those with less than three protease inhibitor mutations. Conclusion: Reduced Bevirimat activity can be expected in one-third of treatment-naive HIV subtype-B isolates and significantly more in protease inhibitor-resistant HIV. These data indicate that screening for Bevirimat resistance mutations before administration of the drug is essential.
The prototype HIV-1 maturation inhibitor, Bevirimat, binds to the CA-SP1 cleavage site in immature Gag particles
Retrovirology 2011 Dec 7;8:101.PMID:22151792DOI:10.1186/1742-4690-8-101.
Background: Bevirimat, the prototype Human Immunodeficiency Virus type 1 (HIV-1) maturation inhibitor, is highly potent in cell culture and efficacious in HIV-1 infected patients. In contrast to inhibitors that target the active site of the viral protease, Bevirimat specifically inhibits a single cleavage event, the final processing step for the Gag precursor where p25 (CA-SP1) is cleaved to p24 (CA) and SP1. Results: In this study, photoaffinity analogs of Bevirimat and mass spectrometry were employed to map the binding site of Bevirimat to Gag within immature virus-like particles. Bevirimat analogs were found to crosslink to sequences overlapping, or proximal to, the CA-SP1 cleavage site, consistent with previous biochemical data on the effect of Bevirimat on Gag processing and with genetic data from resistance mutations, in a region predicted by NMR and mutational studies to have α-helical character. Unexpectedly, a second region of interaction was found within the Major Homology Region (MHR). Extensive prior genetic evidence suggests that the MHR is critical for virus assembly. Conclusions: This is the first demonstration of a direct interaction between the maturation inhibitor, Bevirimat, and its target, Gag. Information gained from this study sheds light on the mechanisms by which the virus develops resistance to this class of drug and may aid in the design of next-generation maturation inhibitors.
Predicting Bevirimat resistance of HIV-1 from genotype
BMC Bioinformatics 2010 Jan 20;11:37.PMID:20089140DOI:10.1186/1471-2105-11-37.
Background: Maturation inhibitors are a new class of antiretroviral drugs. Bevirimat (BVM) was the first substance in this class of inhibitors entering clinical trials. While the inhibitory function of BVM is well established, the molecular mechanisms of action and resistance are not well understood. It is known that mutations in the regions CS p24/p2 and p2 can cause phenotypic resistance to BVM. We have investigated a set of p24/p2 sequences of HIV-1 of known phenotypic resistance to BVM to test whether BVM resistance can be predicted from sequence, and to identify possible molecular mechanisms of BVM resistance in HIV-1. Results: We used artificial neural networks and random forests with different descriptors for the prediction of BVM resistance. Random forests with hydrophobicity as descriptor performed best and classified the sequences with an area under the Receiver Operating Characteristics (ROC) curve of 0.93 +/- 0.001. For the collected data we find that p2 sequence positions 369 to 376 have the highest impact on resistance, with positions 370 and 372 being particularly important. These findings are in partial agreement with other recent studies. Apart from the complex machine learning models we derived a number of simple rules that predict BVM resistance from sequence with surprising accuracy. According to computational predictions based on the data set used, cleavage sites are usually not shifted by resistance mutations. However, we found that resistance mutations could shorten and weaken the alpha-helix in p2, which hints at a possible resistance mechanism. Conclusions: We found that BVM resistance of HIV-1 can be predicted well from the sequence of the p2 peptide, which may prove useful for personalized therapy if maturation inhibitors reach clinical practice. Results of secondary structure analysis are compatible with a possible route to BVM resistance in which mutations weaken a six-helix bundle discovered in recent experiments, and thus ease Gag cleavage by the retroviral protease.