Введение
Класс противовирусных препаратов, используемых для лечения ВИЧ/СПИДа и гепатита С. Ингибиторы протеазы (ПИ) – это лекарственные средства, которые действуют, вмешиваясь в работу ферментов, расщепляющих белки. Некоторые из наиболее известных являются антивирусными препаратами, широко используемыми для лечения ВИЧ/СПИДа, гепатита С и COVID-19. Эти ингибиторы протеазы предотвращают репликацию вируса, селективно связываясь с вирусными протеазами (например, с ВИЧ-1 протеазой) и блокируя протеолитическое расщепление белковых прекурсоров, необходимых для производства инфекционных вирусных частиц. Ингибиторы протеазы, разработанные и в настоящее время используемые в клинической практике, включают:
Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID 19. These protease inhibitors prevent viral replication by 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 that have been developed and are currently used in clinical practice include:
Antiretroviral HIV 1 protease inhibitors—class stem
Amprenavir
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
Hepatitis C virus NS3/4A protease inhibitors—class stem
Ensitrelvir
Nirmatrelvir
Simnotrelvir
Given the specificity of the target of these drugs there is the risk, like with 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. In addition to those non human proteases listed above, inhibitors of human proteases may be used to treat cancer. See the articles matrix metalloproteinase inhibitor and proteasome inhibitor Prior to this the annual death rate had been increasing by approximately 20% each year. Name Trade name Company Patent FDA approval date Notes Saquinavir Invirase, Fortovase Hoffmann–La Roche December 6, 1995 The first protease inhibitor approved by the U. S. Food and Drug Administration (FDA). Ritonavir Norvir AbbVie March 1, 1996 AbbVie was part of Abbott Laboratories when patent was granted. As well as being a protease inhibitor in its own right, ritonavir inhibits the breakdown of other protease inhibitors. This property makes it very useful in drug combinations. Indinavir Crixivan Merck & Co. March 13, 1996 — Nelfinavir Viracept Hoffmann–La Roche March 14, 1997 — Amprenavir Agenerase GlaxoSmithKline April 15, 1999 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 8 very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir. Lopinavir Kaletra AbbVie September 15, 2000 Is only marketed as a fixed dose combination with ritonavir (see lopinavir/ritonavir). AbbVie was part of Abbott Laboratories when patent was granted. Atazanavir Reyataz Bristol Myers Squibb 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 — October 20, 2003 A prodrug of amprenavir. 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 — June 22, 2005 Also known as tipranavir disodium. Darunavir Prezista Janssen Therapeutics June 23, 2006 As of 2016, darunavir 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 darunavir/ritonavir combination being superior to the lopinavir/ritonavir combination for first line therapy. Darunavir is the first drug in a long time that did not come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third.
Ингибиторы протеазы антиретровирусного ВИЧ-1 – класс стволовой
Ампренавир
Атазанавир
Дарнаувир
Фосампренавир
Индинавир
Лопинавир
Нельфинавир
Ритонавир
Саквинавир
Типранавир
Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID 19. These protease inhibitors prevent viral replication by 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 that have been developed and are currently used in clinical practice include:
Antiretroviral HIV 1 protease inhibitors—class stem
Amprenavir
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
Hepatitis C virus NS3/4A protease inhibitors—class stem
Ensitrelvir
Nirmatrelvir
Simnotrelvir
Given the specificity of the target of these drugs there is the risk, like with 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. In addition to those non human proteases listed above, inhibitors of human proteases may be used to treat cancer. See the articles matrix metalloproteinase inhibitor and proteasome inhibitor Prior to this the annual death rate had been increasing by approximately 20% each year. Name Trade name Company Patent FDA approval date Notes Saquinavir Invirase, Fortovase Hoffmann–La Roche December 6, 1995 The first protease inhibitor approved by the U. S. Food and Drug Administration (FDA). Ritonavir Norvir AbbVie March 1, 1996 AbbVie was part of Abbott Laboratories when patent was granted. As well as being a protease inhibitor in its own right, ritonavir inhibits the breakdown of other protease inhibitors. This property makes it very useful in drug combinations. Indinavir Crixivan Merck & Co. March 13, 1996 — Nelfinavir Viracept Hoffmann–La Roche March 14, 1997 — Amprenavir Agenerase GlaxoSmithKline April 15, 1999 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 8 very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir. Lopinavir Kaletra AbbVie September 15, 2000 Is only marketed as a fixed dose combination with ritonavir (see lopinavir/ritonavir). AbbVie was part of Abbott Laboratories when patent was granted. Atazanavir Reyataz Bristol Myers Squibb 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 — October 20, 2003 A prodrug of amprenavir. 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 — June 22, 2005 Also known as tipranavir disodium. Darunavir Prezista Janssen Therapeutics June 23, 2006 As of 2016, darunavir 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 darunavir/ritonavir combination being superior to the lopinavir/ritonavir combination for first line therapy. Darunavir is the first drug in a long time that did not come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third.
Ингибиторы протеазы вируса гепатита С NS3/4A – класс стволовой
Энситрелвир
Нирматрелвир
Симнотрелвир
Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID 19. These protease inhibitors prevent viral replication by 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 that have been developed and are currently used in clinical practice include:
Antiretroviral HIV 1 protease inhibitors—class stem
Amprenavir
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
Hepatitis C virus NS3/4A protease inhibitors—class stem
Ensitrelvir
Nirmatrelvir
Simnotrelvir
Given the specificity of the target of these drugs there is the risk, like with 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. In addition to those non human proteases listed above, inhibitors of human proteases may be used to treat cancer. See the articles matrix metalloproteinase inhibitor and proteasome inhibitor Prior to this the annual death rate had been increasing by approximately 20% each year. Name Trade name Company Patent FDA approval date Notes Saquinavir Invirase, Fortovase Hoffmann–La Roche December 6, 1995 The first protease inhibitor approved by the U. S. Food and Drug Administration (FDA). Ritonavir Norvir AbbVie March 1, 1996 AbbVie was part of Abbott Laboratories when patent was granted. As well as being a protease inhibitor in its own right, ritonavir inhibits the breakdown of other protease inhibitors. This property makes it very useful in drug combinations. Indinavir Crixivan Merck & Co. March 13, 1996 — Nelfinavir Viracept Hoffmann–La Roche March 14, 1997 — Amprenavir Agenerase GlaxoSmithKline April 15, 1999 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 8 very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir. Lopinavir Kaletra AbbVie September 15, 2000 Is only marketed as a fixed dose combination with ritonavir (see lopinavir/ritonavir). AbbVie was part of Abbott Laboratories when patent was granted. Atazanavir Reyataz Bristol Myers Squibb 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 — October 20, 2003 A prodrug of amprenavir. 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 — June 22, 2005 Also known as tipranavir disodium. Darunavir Prezista Janssen Therapeutics June 23, 2006 As of 2016, darunavir 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 darunavir/ritonavir combination being superior to the lopinavir/ritonavir combination for first line therapy. Darunavir is the first drug in a long time that did not come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third.
Учитывая специфичность мишени этих препаратов, существует риск, как и при использовании антибиотиков, развития лекарственно-устойчивых мутировавших вирусов. Для снижения этого риска обычно применяют несколько различных препаратов одновременно, каждый из которых направлен на разные мишени. Помимо перечисленных выше нечеловеческих протеаз, ингибиторы человеческих протеаз могут использоваться для лечения рака. См. статьи «Ингибитор матриксных металлопротеиназ» и «Ингибитор протеасомы». До этого ежегодный уровень смертности увеличивался примерно на 20% в год.
Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID 19. These protease inhibitors prevent viral replication by 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 that have been developed and are currently used in clinical practice include:
Antiretroviral HIV 1 protease inhibitors—class stem
Amprenavir
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
Hepatitis C virus NS3/4A protease inhibitors—class stem
Ensitrelvir
Nirmatrelvir
Simnotrelvir
Given the specificity of the target of these drugs there is the risk, like with 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. In addition to those non human proteases listed above, inhibitors of human proteases may be used to treat cancer. See the articles matrix metalloproteinase inhibitor and proteasome inhibitor Prior to this the annual death rate had been increasing by approximately 20% each year. Name Trade name Company Patent FDA approval date Notes Saquinavir Invirase, Fortovase Hoffmann–La Roche December 6, 1995 The first protease inhibitor approved by the U. S. Food and Drug Administration (FDA). Ritonavir Norvir AbbVie March 1, 1996 AbbVie was part of Abbott Laboratories when patent was granted. As well as being a protease inhibitor in its own right, ritonavir inhibits the breakdown of other protease inhibitors. This property makes it very useful in drug combinations. Indinavir Crixivan Merck & Co. March 13, 1996 — Nelfinavir Viracept Hoffmann–La Roche March 14, 1997 — Amprenavir Agenerase GlaxoSmithKline April 15, 1999 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 8 very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir. Lopinavir Kaletra AbbVie September 15, 2000 Is only marketed as a fixed dose combination with ritonavir (see lopinavir/ritonavir). AbbVie was part of Abbott Laboratories when patent was granted. Atazanavir Reyataz Bristol Myers Squibb 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 — October 20, 2003 A prodrug of amprenavir. 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 — June 22, 2005 Also known as tipranavir disodium. Darunavir Prezista Janssen Therapeutics June 23, 2006 As of 2016, darunavir 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 darunavir/ritonavir combination being superior to the lopinavir/ritonavir combination for first line therapy. Darunavir is the first drug in a long time that did not come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third.
Название | Торговое наименование | Компания | Патент | Дата одобрения FDA | Примечания
---|---|---|---|---|---
Саквинавир | Инвиразе, Фортовазе | Hoffmann–La Roche | | 6 декабря 1995 | Первый ингибитор протеазы, одобренный Управлением по контролю за продуктами и лекарствами США (FDA).
Ритонавир | Норвир | AbbVie | | 1 марта 1996 | AbbVie входила в Abbott Laboratories на момент выдачи патента. Ритонавир, помимо собственной активности в качестве ингибитора протеазы, ингибирует распад других ингибиторов протеазы. Это свойство делает его очень полезным в комбинированных схемах лечения.
Индинавир | Криксиван | Merck & Co. | | 13 марта 1996 |
Нельфинавир | Вирасепт | Hoffmann–La Roche | | 14 марта 1997 |
Ампренавир | Агенераза | GlaxoSmithKline | | 15 апреля 1999 | Шестнадцатый антиретровирусный препарат, одобренный FDA. Это был первый ингибитор протеазы, одобренный для приема два раза в день вместо каждых восьми часов. Удобный режим дозирования был дорогостоящим, поскольку требуемая доза составляет 1200 мг, доставляемая в 8 очень больших гелевых капсулах. Производство было прекращено производителем 31 декабря 2004 года, поскольку препарат был заменен фосампренавиром.
Лопинавир | Калетра | AbbVie | | 15 сентября 2000 | Выпускается только в виде фиксированной комбинации с ритонавиром (см. Лопинавир/ритонавир). AbbVie входила в Abbott Laboratories на момент выдачи патента.
Атазанавир | Reyataz | Bristol Myers Squibb | | 20 июня 2003 | Атазанавир был первым ПИ, одобренным для приема один раз в день. По-видимому, он реже вызывает липодистрофию и повышение уровня холестерина в качестве побочных эффектов. Также может не проявлять перекрестную устойчивость к другим ПИ.
Фосампренавир | Lexiva, Telzir | GlaxoSmithKline | | 20 октября 2003 | Пролекарство ампренавира. Организм человека метаболизирует фосампренавир с образованием ампренавира, который является активным ингредиентом. Этот метаболизм увеличивает продолжительность доступности ампренавира, делая фосампренавир препаратом пролонгированного действия и, следовательно, уменьшая количество необходимых таблеток по сравнению со стандартным ампренавиром.
Типранавир | Aptivus | Boehringer Ingelheim | | 22 июня 2005 | Также известен как типранавир динатрия.
Дарнаувир | Prezista | Janssen Therapeutics | | 23 июня 2006 | По состоянию на 2016 год дарнаувир является рекомендованным вариантом лечения OARAC для пациентов, ранее не получавших лечение, а также для взрослых и подростков с опытом лечения. Несколько текущих исследований фазы III показывают высокую эффективность комбинации дарнаувир/ритонавир, превосходящую комбинацию лопинавир/ритонавир в качестве терапии первой линии. Дарнаувир – первый препарат за долгое время, который не сопровождался повышением цены. Он обогнал два других одобренных препарата аналогичного типа и соответствует цене третьего.
Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID 19. These protease inhibitors prevent viral replication by 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 that have been developed and are currently used in clinical practice include:
Antiretroviral HIV 1 protease inhibitors—class stem
Amprenavir
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
Hepatitis C virus NS3/4A protease inhibitors—class stem
Ensitrelvir
Nirmatrelvir
Simnotrelvir
Given the specificity of the target of these drugs there is the risk, like with 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. In addition to those non human proteases listed above, inhibitors of human proteases may be used to treat cancer. See the articles matrix metalloproteinase inhibitor and proteasome inhibitor Prior to this the annual death rate had been increasing by approximately 20% each year. Name Trade name Company Patent FDA approval date Notes Saquinavir Invirase, Fortovase Hoffmann–La Roche December 6, 1995 The first protease inhibitor approved by the U. S. Food and Drug Administration (FDA). Ritonavir Norvir AbbVie March 1, 1996 AbbVie was part of Abbott Laboratories when patent was granted. As well as being a protease inhibitor in its own right, ritonavir inhibits the breakdown of other protease inhibitors. This property makes it very useful in drug combinations. Indinavir Crixivan Merck & Co. March 13, 1996 — Nelfinavir Viracept Hoffmann–La Roche March 14, 1997 — Amprenavir Agenerase GlaxoSmithKline April 15, 1999 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 8 very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir. Lopinavir Kaletra AbbVie September 15, 2000 Is only marketed as a fixed dose combination with ritonavir (see lopinavir/ritonavir). AbbVie was part of Abbott Laboratories when patent was granted. Atazanavir Reyataz Bristol Myers Squibb 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 — October 20, 2003 A prodrug of amprenavir. 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 — June 22, 2005 Also known as tipranavir disodium. Darunavir Prezista Janssen Therapeutics June 23, 2006 As of 2016, darunavir 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 darunavir/ritonavir combination being superior to the lopinavir/ritonavir combination for first line therapy. Darunavir is the first drug in a long time that did not come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third.
Неантиретровирусная антивирусная активность
Комбинация лекарственных средств для лечения SARS-CoV-2, Paxlovid, разработанная компанией Pfizer, была одобрена 22 декабря 2021 года. Она состоит из нирматрелвира, ингибитора протеазы, нацеленного на 3C-подобную протеазу SARS-CoV-2, и ритонавира, который подавляет метаболизм нирматрелвира. Ингибиторы протеазы также применяются для лечения гепатита С.
Противоопухолевая активность
Исследователи изучают возможность использования ингибиторов протеазы для лечения рака. Например, нельфинавир и атазанавир способны уничтожать опухолевые клетки в культуре (в чашке Петри). Этот эффект пока не изучался на людях, но исследования на лабораторных мышах показали, что нельфинавир способен подавлять рост опухолей у этих животных, что является перспективным направлением для тестирования этого препарата на людях. Эта липодистрофия в разговорной речи известна как "живот Крикса", по названию индинавира (Crixivan).