Category:Antivirals: Difference between revisions
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The clinical use of antiviral medicines began in 1962 with [[wikipedia:Idoxuridine|idoxuridine]], a halogenated pyrimidine analogue developed by [[wikipedia:William Prusoff|William Prusoff]] at Yale as a potential anticancer agent that was found instead to inhibit herpes simplex virus DNA polymerase; it became the first topical treatment for herpetic keratitis. The medicine was too toxic for systemic use, but it established the principle: a nucleoside analogue that the viral enzyme preferentially incorporated into nascent viral DNA, but that the corresponding human enzyme rejected, could selectively kill the virus. | The clinical use of antiviral medicines began in 1962 with [[wikipedia:Idoxuridine|idoxuridine]], a halogenated pyrimidine analogue developed by [[wikipedia:William Prusoff|William Prusoff]] at Yale as a potential anticancer agent that was found instead to inhibit herpes simplex virus DNA polymerase; it became the first topical treatment for herpetic keratitis. The medicine was too toxic for systemic use, but it established the principle: a nucleoside analogue that the viral enzyme preferentially incorporated into nascent viral DNA, but that the corresponding human enzyme rejected, could selectively kill the virus. | ||
The first effective systemic antiviral was the work of [[wikipedia:Gertrude B. Elion|Gertrude Elion]] and her colleagues at Burroughs Wellcome. Elion had spent decades developing purine and pyrimidine analogues for cancer chemotherapy ([[wikipedia:Mercaptopurine|6-mercaptopurine]], [[wikipedia:Azathioprine|azathioprine]], allopurinol); in the 1970s the same screening framework was turned toward viral enzymes. [[wikipedia:Aciclovir|Aciclovir]] (acyclovir), reported in 1977, was an acyclic guanosine analogue that required phosphorylation by the herpes simplex virus thymidine kinase to its monophosphate, then by cellular kinases to the triphosphate, which selectively inhibited the viral DNA polymerase.<ref name="elion1977">Elion GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L, Schaeffer HJ. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine. ''Proceedings of the National Academy of Sciences of the United States of America''. 1977 Dec;74(12):5716-5720. PMID 202961.</ref> Because the host cell did not phosphorylate the medicine to any meaningful extent, aciclovir was concentrated, by orders of magnitude, in herpes-infected cells. The selectivity was extraordinary, and the medicine remains the standard treatment for herpes simplex and herpes zoster decades later. Elion shared the 1988 Nobel Prize. [[Valacyclovir|Valacyclovir]] (the L-valyl ester | The first effective systemic antiviral was the work of [[wikipedia:Gertrude B. Elion|Gertrude Elion]] and her colleagues at Burroughs Wellcome. Elion had spent decades developing purine and pyrimidine analogues for cancer chemotherapy ([[wikipedia:Mercaptopurine|6-mercaptopurine]], [[wikipedia:Azathioprine|azathioprine]], allopurinol); in the 1970s the same screening framework was turned toward viral enzymes. [[wikipedia:Aciclovir|Aciclovir]] (acyclovir), reported in 1977, was an acyclic guanosine analogue that required phosphorylation by the herpes simplex virus thymidine kinase to its monophosphate, then by cellular kinases to the triphosphate, which selectively inhibited the viral DNA polymerase.<ref name="elion1977">Elion GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L, Schaeffer HJ. Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine. ''Proceedings of the National Academy of Sciences of the United States of America''. 1977 Dec;74(12):5716-5720. PMID 202961.</ref> Because the host cell did not phosphorylate the medicine to any meaningful extent, aciclovir was concentrated, by orders of magnitude, in herpes-infected cells. The selectivity was extraordinary, and the medicine remains the standard treatment for herpes simplex and herpes zoster decades later. Elion shared the 1988 Nobel Prize. [[Valacyclovir|Valacyclovir]] (the L-valyl ester, 1995) and famciclovir (the diacetyl ester of penciclovir, 1994) improved oral bioavailability without changing the underlying pharmacology. | ||
The transformative antiviral event of the late twentieth century was the introduction of antiretroviral therapy for human immunodeficiency virus. [[wikipedia:Zidovudine|Zidovudine]] (azidothymidine, AZT) had been synthesised by Jerome Horwitz in 1964 as a failed anticancer agent. In 1985 [[wikipedia:Hiroaki Mitsuya|Hiroaki Mitsuya]] and [[wikipedia:Samuel Broder|Samuel Broder]] at the National Cancer Institute, screening Horwitz's old compound collection, showed that AZT inhibited HIV reverse transcriptase in vitro; the medicine was rushed through trial and approved in 1987, becoming the first antiretroviral.<ref name="mitsuya1985">Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. ''Proceedings of the National Academy of Sciences of the United States of America''. 1985 Oct;82(20):7096-7100. PMID 2413459.</ref> Monotherapy with zidovudine produced rapid resistance and limited survival benefit; the breakthrough was the 1996 introduction of three-medicine "highly active antiretroviral therapy" (HAART), in which two nucleoside reverse transcriptase inhibitors were combined with either a protease inhibitor (saquinavir, ritonavir, indinavir, nelfinavir) or a non-nucleoside reverse transcriptase inhibitor (nevirapine, efavirenz). HAART converted HIV infection from a uniformly fatal disease (median survival approximately 10 years after seroconversion before 1996) to a chronic manageable condition with near-normal life expectancy on continuous treatment. Subsequent classes (the integrase strand transfer inhibitors raltegravir, dolutegravir, bictegravir; the fusion inhibitors and entry inhibitors maraviroc, enfuvirtide; the capsid inhibitor lenacapavir) and once-daily fixed-dose combination tablets have made modern antiretroviral therapy a single pill, taken once a day, with minimal side effect. | The transformative antiviral event of the late twentieth century was the introduction of antiretroviral therapy for human immunodeficiency virus. [[wikipedia:Zidovudine|Zidovudine]] (azidothymidine, AZT) had been synthesised by Jerome Horwitz in 1964 as a failed anticancer agent. In 1985 [[wikipedia:Hiroaki Mitsuya|Hiroaki Mitsuya]] and [[wikipedia:Samuel Broder|Samuel Broder]] at the National Cancer Institute, screening Horwitz's old compound collection, showed that AZT inhibited HIV reverse transcriptase in vitro; the medicine was rushed through trial and approved in 1987, becoming the first antiretroviral.<ref name="mitsuya1985">Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. ''Proceedings of the National Academy of Sciences of the United States of America''. 1985 Oct;82(20):7096-7100. PMID 2413459.</ref> Monotherapy with zidovudine produced rapid resistance and limited survival benefit; the breakthrough was the 1996 introduction of three-medicine "highly active antiretroviral therapy" (HAART), in which two nucleoside reverse transcriptase inhibitors were combined with either a protease inhibitor (saquinavir, ritonavir, indinavir, nelfinavir) or a non-nucleoside reverse transcriptase inhibitor (nevirapine, efavirenz). HAART converted HIV infection from a uniformly fatal disease (median survival approximately 10 years after seroconversion before 1996) to a chronic manageable condition with near-normal life expectancy on continuous treatment. Subsequent classes (the integrase strand transfer inhibitors raltegravir, dolutegravir, bictegravir; the fusion inhibitors and entry inhibitors maraviroc, enfuvirtide; the capsid inhibitor lenacapavir) and once-daily fixed-dose combination tablets have made modern antiretroviral therapy a single pill, taken once a day, with minimal side effect. | ||
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* '''Herpesvirus medicines''' ([[:Category:Anti-herpesvirus_agents|anti-herpesvirus agents]], herpes simplex and varicella zoster): [[Acyclovir|aciclovir (acyclovir)]] and its valyl | * '''Herpesvirus medicines''' ([[:Category:Anti-herpesvirus_agents|anti-herpesvirus agents]], herpes simplex and varicella zoster): [[Acyclovir|aciclovir (acyclovir)]] and its valyl ester [[Valacyclovir|valaciclovir]]; famciclovir (the diacetyl ester of penciclovir); for cytomegalovirus the more potent ganciclovir and valganciclovir, with foscarnet for resistant CMV and the recent letermovir | ||
* '''Influenza medicines''' ([[:Category:Anti-influenza_agents|anti-influenza agents]] and [[:Category:Neuraminidase_inhibitors|neuraminidase inhibitors]]): [[Oseltamivir|oseltamivir]], zanamivir, peramivir (intravenous), baloxavir (cap-dependent endonuclease inhibitor) | * '''Influenza medicines''' ([[:Category:Anti-influenza_agents|anti-influenza agents]] and [[:Category:Neuraminidase_inhibitors|neuraminidase inhibitors]]): [[Oseltamivir|oseltamivir]], zanamivir, peramivir (intravenous), baloxavir (cap-dependent endonuclease inhibitor) | ||
* '''Antiretrovirals''' (HIV): the nucleoside / nucleotide reverse transcriptase inhibitors (zidovudine, lamivudine, abacavir, tenofovir alafenamide and disoproxil fumarate, emtricitabine), the non-nucleoside reverse transcriptase inhibitors (efavirenz, rilpivirine, doravirine), the protease inhibitors (ritonavir as booster, darunavir, atazanavir), the integrase strand transfer inhibitors (raltegravir, dolutegravir, bictegravir, cabotegravir), the entry and fusion inhibitors (maraviroc, enfuvirtide), the capsid inhibitor lenacapavir, and the long-acting injectable cabotegravir/rilpivirine | * '''Antiretrovirals''' (HIV): the nucleoside / nucleotide reverse transcriptase inhibitors (zidovudine, lamivudine, abacavir, tenofovir alafenamide and disoproxil fumarate, emtricitabine), the non-nucleoside reverse transcriptase inhibitors (efavirenz, rilpivirine, doravirine), the protease inhibitors (ritonavir as booster, darunavir, atazanavir), the integrase strand transfer inhibitors (raltegravir, dolutegravir, bictegravir, cabotegravir), the entry and fusion inhibitors (maraviroc, enfuvirtide), the capsid inhibitor lenacapavir, and the long-acting injectable cabotegravir/rilpivirine | ||