HIV protease inhibitors

関

Protease inhib- itors)

WordNet

1. a substance that retards or stops an activity
2. the 8th letter of the Roman alphabet (同)h
3. any enzyme that catalyzes the splitting of proteins into smaller peptide fractions and amino acids by a process known as proteolysis (同)peptidase, proteinase, proteolytic_enzyme
4. infection by the human immunodeficiency virus
5. any tropical African shrub of the genus Protea having alternate rigid leaves and dense colorful flower heads resembling cones

PrepTutorEJDIC

1. 抑制する人(物) / 化学反応抑制剤
2. hydrogenの化学記号
3. 鉛筆の硬度 / 《俗》heroin

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/01/24 00:15:33」(JST)

wiki en

[Wiki en表示]

For natural protease inhibitors, see protease inhibitor (biology).

Protease inhibitors (PIs) are a class of antiviral drugs that are widely used to treat HIV/AIDS and hepatitis caused by hepatitis C virus. Protease inhibitors prevent viral replication selectively binding to viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.

Protease inhibitors have been developed or are presently undergoing testing for treating various viruses:

• HIV/AIDS: antiretroviral protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir, amprenavir etc.)
• Hepatitis C: boceprevir, telaprevir , simeprevir

Given the specificity of the target of these drugs there is the risk, as in antibiotics, of the development of drug-resistant mutated viruses. To reduce this risk it is common to use several different drugs together that are each aimed at different targets.

Antiretrovirals

Protease inhibitors were the second class of antiretroviral drugs developed. The first members of this class, saquinavir (Hoffman-La Roche) and ritonavir (Abbott), were approved in late 1995-1996. Within 2 years, annual deaths from AIDS in the United States fell from over 50,000 to approximately 18,000 Prior to this the annual death rate had been increasing by approximately 20% each year.

Name	Trade name	Company	Patent	Notes
Saquinavir	Fortovase, Invirase	Hoffmann–La Roche	U.S. Patent 5,196,438	It was the first protease inhibitor approved by the FDA (December 6, 1995).
Ritonavir	Norvir	Abbott Laboratories	U.S. Patent 5,541,206	-
Indinavir	Crixivan	Merck & Co.	U.S. Patent 5,413,999	-
Nelfinavir	Viracept	Agouron Pharmaceuticals	U.S. Patent 5,484,926	-
Amprenavir	Agenerase	GlaxoSmithKline	U.S. Patent 5,585,397	The FDA approved it April 15, 1999, making it the sixteenth FDA-approved antiretroviral. It was the first protease inhibitor approved for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir.
Lopinavir	Kaletra	Abbott	U.S. Patent 5,914,332	Is only marketed as a combination, with ritonavir.
Atazanavir	Reyataz	Bristol-Myers Squibb	U.S. Patent 5,849,911	The FDA approved it on June 20, 2003. Atazanavir was the first PI approved for once-daily dosing. It appears to be less likely to cause lipodystrophy and elevated cholesterol as side effects. It may also not be cross-resistant with other PIs.
Fosamprenavir	Lexiva, Telzir	GlaxoSmithKline	-	Is a prodrug of amprenavir. The FDA approved it October 20, 2003. The human body metabolizes fosamprenavir in order to form amprenavir, which is the active ingredient. That metabolization increases the duration that amprenavir is available, making fosamprenavir a slow-release version of amprenavir and thus reduces the number of pills required versus standard amprenavir.
Tipranavir	Aptivus	Boehringer-Ingelheim	-	Also known as tipranavir disodium
Darunavir	Prezista	Tibotec	U.S. Patent 6,248,775	It was approved by the Food and Drug Administration (FDA) on June 23, 2006. Prezista is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents. Several ongoing phase III trials are showing a high efficiency for the PREZISTA/rtv combination being superior to the lopinavir/rtv combination for first-line therapy. Darunavir is the first drug in a long time that didn't come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third.
Simeprevir	Olysio, formerly TMC435	Medivir & Johnson & Johnson	U.S. Patent 7,671,032	Simeprevir is a NS3/4A protease inhibitor

Antiprotozoal activity

Researchers are investigating the use of protease inhibitors developed for HIV treatment as anti-protozoals for use against malaria and gastrointestinal protozoal infections:

• A combination of ritonavir and lopinavir was found to have some effectiveness against Giardia infection.
• The drugs saquinavir, ritonavir, and lopinavir have been found to have anti-malarial properties.
• A cysteine protease inhibitor drug was found to cure Chagas disease in mice.

Anticancer activity

Researchers are investigating whether protease inhibitors could possibly be used to treat cancer. For example, nelfinavir and atazanavir are able to kill tumor cells in culture (in a Petri dish). This effect has not yet been examined in humans; but studies in laboratory mice have shown that nelfinavir is able to suppress the growth of tumors in these animals, which represents a promising lead towards testing this drug in humans as well.

Inhibitors of the proteasome, such as Velcade/Bortezomib are now front-line drugs for the treatment of various cancers, notably Multiple Myeloma.

Side effects

Protease inhibitors can cause a syndrome of lipodystrophy, hyperlipidaemia, diabetes mellitus type 2, and kidney stones. This lipodystrophy is colloquially known as "Crix belly", after Crixivan.

See also

• David Ho - AIDS researcher who pioneered the use of protease inhibitors in treating HIV-infected patients
• The Proteolysis Map
• Reverse transcriptase inhibitor

References

External links

• A brief history of the development of protease inhibitors by Hoffman La Roche, Abbott, and Merck

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. HIVプロテアーゼ阻害剤 hiv protease inhibitors
• 2. HIV抗レトロウイルス療法に関する臨床試験：プロテアーゼ阻害剤 clinical trials of hiv antiretroviral therapy protease inhibitors
• 3. HIV抗レトロウイルス療法に関する臨床試験：プロテアーゼ阻害剤と非ヌクレオシド系逆転写酵素阻害剤の比較 clinical trials of hiv antiretroviral therapy protease inhibitors versus non nucleoside reverse transcriptase inhibitors
• 4. HIV-2感染の治療 treatment of hiv 2 infection
• 5. 未治療HIV感染患者のための抗レトロウイルス療法の選択 selecting antiretroviral regimens for the treatment naive hiv infected patient

English Journal

• Quantitative assessment of in vivo HIV protease activity using genetically engineered QD-based FRET probes.

• Cella LN1, Biswas P, Yates MV, Mulchandani A, Chen W.Author information 1Department of Chemical and Environmental Engineering, University of California, Riverside, California.AbstractHIV protease plays a central role in its life cycle leading to release of functional viral particles. It has been successfully used as a therapeutic target to block HIV infection. Several protease inhibitors (PIs) are currently being employed as a part of anti-HIV therapy. However, the constant genetic drift in the virus leads to accumulation of mutations in both cleavage site and the protease, resulting in resistance and failure of therapy. We reported the use of a quantum dot (QD)-based protein probe for the in vivo monitoring of HIV-1 protease activity based on fluorescence resonance energy transfer. In the current study, we demonstrate the utility of this approach by quantifying the in vivo cleavage rates of three known protease and cleavage site mutations in the presence or absence of different PIs. The changes in IC50 values for the different PIs were similar to that observed in patients, validating our assay as a rapid platform for PI screening. Biotechnol. Bioeng. 2014;111: 1082-1087. © 2014 Wiley Periodicals, Inc.
• Biotechnology and bioengineering.Biotechnol Bioeng.2014 Jun;111(6):1082-7. doi: 10.1002/bit.25199. Epub 2014 Feb 21.
• HIV protease plays a central role in its life cycle leading to release of functional viral particles. It has been successfully used as a therapeutic target to block HIV infection. Several protease inhibitors (PIs) are currently being employed as a part of anti-HIV therapy. However, the constant gene
• PMID 24473897

• Advances in Non-peptidomimetic HIV Protease Inhibitors.

• Pang X, Liu Z, Zhai G1.Author information 1Department of Pharmaceutics, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China. professorgxzhai@126.com.AbstractHIV protease plays a crucial role in the viral life cycle. It can cleave a series of heptamers in the viral Gag and GagPol precursor proteins to generate mature infectious virus particles. Successful inhibition of the protease will prevent this maturation step and hence block the spreading of HIV. However, the rapid emergence of drug resistance makes it urgent to develop new HIV protease inhibitors to combat the global disease. Besides, poor oral bioavailability, unacceptable side effects, high treatment cost and pill burden also trouble the application of HIV protease inhibitors. In such situations, non-peptidomimetic HIV protease inhibitors have drawn an increasing interest as a potential therapeutic option due to their small molecular weight, favorable bioavailability, high stability in vivo, low resistance and cost of production. In this review, we present the recent advances in non-peptidomimetic HIV protease inhibitors. Their design strategies, biological activities, resistance profiles, as well as clinical application will also be discussed.
• Current medicinal chemistry.Curr Med Chem.2014 Jun;21(17):1997-2011.
• HIV protease plays a crucial role in the viral life cycle. It can cleave a series of heptamers in the viral Gag and GagPol precursor proteins to generate mature infectious virus particles. Successful inhibition of the protease will prevent this maturation step and hence block the spreading of HIV. H
• PMID 24533811

• Binary and ternary combinations of anti-HIV protease inhibitors: effect on gene expression and functional activity of CYP3A4 and efflux transporters.

• Kwatra D, Vadlapudi AD, Vadlapatla RK, Khurana V, Pal D, Mitra AK.AbstractAbstract Background: The purpose of this study is to identify the effect of binary and ternary combinations of anti-HIV protease inhibitors (PIs) on the expression of metabolizing enzyme (CYP3A4) and efflux transporters [multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)] in a model intestinal cell line (LS-180). Methods: LS-180 cells were treated with various combinations of PIs (amprenavir, indinavir, saquinavir and lopinavir), and the mRNA expression levels of metabolizing enzyme and efflux transporters were measured using quantitative reverse transcription polymerase chain reaction. The alteration of gene expression was further correlated to the expression of nuclear hormone receptor PXR. Uptake of fluorescent and radioactive substrates was carried out to study the functional activity of these proteins. Cytotoxicity and adenosine triphosphate (ATP) assays were carried out to measure stress responses. Results: Binary and ternary combinations of PIs appeared to modulate the expression of CYP3A4, MRP2, P-gp and BCRP in a considerable manner. Unlike the individual PIs, their binary combinations showed much greater induction of metabolizing enzyme and efflux proteins. However, such pronounced induction was not observed in the presence of ternary combinations. The observed trend of altered mRNA expression was found to correlate well with the change in expression levels of PXR. The gene expression was found to correlate with activity assays. Lack of cytotoxicity and ATP activity was observed in the treatment samples, suggesting that these alterations in expression levels were probably not stress responses. Conclusions: In the present study, we demonstrated that combinations of drugs can have serious consequences toward the treatment of HIV infection by altering their bioavailability and disposition.
• Drug metabolism and drug interactions.Drug Metabol Drug Interact.2014 Jun 1;29(2):101-10. doi: 10.1515/dmdi-2013-0056.
• Abstract Background: The purpose of this study is to identify the effect of binary and ternary combinations of anti-HIV protease inhibitors (PIs) on the expression of metabolizing enzyme (CYP3A4) and efflux transporters [multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp) and bre
• PMID 24399676

Japanese Journal

• HIVのプロテアーゼ阻害剤(PI)耐性獲得機構の解析と新規PI開発への応用 (第14回日本エイズ学会ECC山口メモリアルエイズ研究奨励賞受賞研究)

• 青木 学
• 日本エイズ学会誌 = The journal of AIDS research 16(2), 77-83, 2014
• NAID 40020114200

• 日本感染症医薬品協会奨励賞受賞講演会記録 2012年度受賞講演 HIVプロテアーゼの2量体形成機構の解析と新規のHIVプロテアーゼ2量体形成阻害剤の開発

• 閌 康博
• The Japanese journal of antibiotics 66(1), 45-53, 2013-02
• NAID 40019599288

• 抗HIV治療薬

• 鯉渕 智彦
• ウイルス 63(2), 199-208, 2013
• … 抗HIV治療薬は，逆転写酵素阻害薬，プロテアーゼ阻害薬（PI: protease inhibitor），インテグラーゼ阻害薬（INSTI: integrase strand transfer inhibitor），侵入阻害薬（CCR5阻害薬）に大別され，さらに逆転写酵素阻害薬はヌクレオシド系（NRTI: nucleoside/nucleotide reverse transcriptase inhibitor）と非ヌクレオシド系(NNRTI: non-nucleoside reverse transcriptase inhibitor) に分けられる．異なる作用機序の薬剤を適切に組み合わせれば長期 …
• NAID 130004713425

Related Links

• Protease Inhibitors (PIs)

A list of the currently available HIV medications ... What are Protease Inhibitors (PIs)? When HIV infects a CD4 cell in a person's body, it copies its own genetic code into the cell's DNA. The CD4 cell is then "programmed" to make ...

• Protease inhibitors - HIV & AIDS Information :: Home

HIV and related materials, including patient information booklets, email bulletins, listings of HIV services, reference materials for professionals working in HIV, books, posters and illustrated leaflets ... Protease inhibitors ...

Related Pictures

---

★リンクテーブル★

関連記事	「inhibitor」「HIV」「H」「HI」

「inhibitor」

　　[★]

• n.

• 阻害剤、阻害薬、抑制薬、抑制剤、(内在性物質について)インヒビター、抑制物質

関

blocker、depressant、suppressant

　 　

「HIV」

　　[★] human immunodeficiency virus HIVウイルス ヒト免疫不全ウイルス 　

「H」

　　[★]

• 食道裂孔
• ヒスチジン
• 水素

　 　 　

「HI」

　　[★] 赤血球凝集抑制試験