Editing Antiviral drug (section)

===Approaches by virus life cycle stage===
[[Virus]]es consist of a [[genome]] and sometimes a few [[enzyme]]s stored in a capsule made of [[protein]] (called a [[capsid]]), and sometimes covered with a [[lipid]] layer (sometimes called an 'envelope'). Viruses cannot reproduce on their own and instead propagate by subjugating a host cell to produce copies of themselves, thus producing the next generation.

Researchers working on such "[[rational drug design]]" strategies for developing antivirals have tried to attack viruses at every stage of their life cycles. Some species of mushrooms have been found to contain multiple antiviral chemicals with similar synergistic effects.<ref>{{cite journal|last1=Lindequist|first1=Ulrike|last2=Niedermeyer|first2=Timo H. J.|last3=Jülich|first3=Wolf-Dieter|year=2005|title=The Pharmacological Potential of Mushrooms|journal=Evidence-Based Complementary and Alternative Medicine|volume=2|issue=3|pages=285–99|doi=10.1093/ecam/neh107|pmc=1193547|pmid=16136207}}</ref>
Compounds isolated from fruiting bodies and filtrates of various mushrooms have broad-spectrum antiviral activities, but successful production and availability of such compounds as frontline antiviral is a long way away.<ref>{{Citation|last1=Pradeep|first1=Prabin|title=Antiviral Potency of Mushroom Constituents|date=2019|work=Medicinal Mushrooms: Recent Progress in Research and Development|pages=275–97|editor-last=Agrawal|editor-first=Dinesh Chandra|publisher=Springer Singapore|language=en|doi=10.1007/978-981-13-6382-5_10|isbn=978-981-13-6382-5|last2=Manju|first2=Vidya|last3=Ahsan|first3=Mohammad Feraz|s2cid=181538245|editor2-last=Dhanasekaran|editor2-first=Muralikrishnan}}</ref>

Viral life cycles vary in their precise details depending on the type of virus, but they all share a general pattern:
# Attachment to a host cell.
# Release of viral genes and possibly enzymes into the host cell.
# Replication of viral components using host-cell machinery.
# Assembly of viral components into complete viral particles.
# Release of viral particles to infect new host cells.

====Before cell entry====
One antiviral strategy is to interfere with the ability of a virus to infiltrate a target cell. The virus must go through a sequence of steps to do this, beginning with binding to a specific "[[receptor (biology)|receptor]]" molecule on the surface of the host cell and ending with the virus "uncoating" inside the cell and releasing its contents. Viruses that have a lipid envelope must also fuse their envelope with the target cell, or with a vesicle that transports them into the cell before they can uncoat.

This stage of viral replication can be inhibited in two ways:
# Using agents which mimic the virus-associated protein (VAP) and bind to the cellular receptors. This may include VAP [[anti-idiotypic]] antibodies, natural [[ligand]]s of the receptor, and anti-receptor antibodies.
# Using agents which mimic the cellular receptor and bind to the VAP. This includes anti-VAP [[antibody|antibodies]], receptor anti-idiotypic antibodies, extraneous receptor and synthetic receptor mimics.

This strategy of designing drugs can be very expensive, and since the process of generating anti-idiotypic antibodies is partly trial and error, it can be a relatively slow process until an adequate molecule is produced.

=====Entry inhibitor=====
{{Main|Entry inhibitor}}
A very early stage of viral infection is [[viral entry]], when the virus attaches to and enters the host cell. A number of "entry-inhibiting" or "entry-blocking" drugs are being developed to fight HIV. HIV most heavily targets a specific type of lymphocyte known as "helper T cells", and identifies these target cells through T-cell surface receptors designated "[[CD4]]" and "[[CCR5]]". Attempts to interfere with the binding of HIV with the CD4 receptor have failed to stop HIV from infecting helper T cells, but research continues on trying to interfere with the binding of HIV to the CCR5 receptor in hopes that it will be more effective.

HIV infects a cell through fusion with the cell membrane, which requires two different cellular molecular participants, CD4 and a chemokine receptor (differing depending on the cell type). Approaches to blocking this virus/cell fusion have shown some promise in preventing entry of the virus into a cell. At least one of these entry inhibitors—a biomimetic peptide called [[Enfuvirtide]], or the brand name Fuzeon—has received FDA approval and has been in use for some time. Potentially, one of the benefits from the use of an effective entry-blocking or entry-inhibiting agent is that it potentially may not only prevent the spread of the virus within an infected individual but also the spread from an infected to an uninfected individual.

One possible advantage of the therapeutic approach of blocking viral entry (as opposed to the currently dominant approach of viral enzyme inhibition) is that it may prove more difficult for the virus to develop resistance to this therapy than for the virus to mutate or evolve its enzymatic protocols.

=====Uncoating inhibitors=====
Inhibitors of uncoating have also been investigated.<ref name="pmid10325536">{{cite journal |author=Bishop NE |title=Examination of potential inhibitors of hepatitis A virus uncoating |journal=Intervirology |volume=41 |issue=6 |pages=261–71 |year=1998 |pmid=10325536 |doi= 10.1159/000024948|s2cid=21222121 }}</ref><ref name="pmid1850030">{{cite journal |vauthors=Almela MJ, González ME, Carrasco L |title=Inhibitors of poliovirus uncoating efficiently block the early membrane permeabilization induced by virus particles |journal=J. Virol. |volume=65 |issue=5 |pages=2572–77 |date=May 1991 |pmid=1850030 |pmc=240614|doi=10.1128/JVI.65.5.2572-2577.1991 }}</ref>

[[Amantadine]] and [[rimantadine]] have been introduced to combat influenza. These agents act on penetration and uncoating.<ref name="isbn0-7817-4673-6">{{cite book |author1=Beringer, Paul |author2=Troy, David A. |author3=Remington, Joseph P. |title=Remington, the science and practice of pharmacy |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2006 |page=1419 |isbn=978-0-7817-4673-1}}</ref>

[[Pleconaril]] works against [[rhinovirus]]es, which cause the [[common cold]], by blocking a pocket on the surface of the virus that controls the uncoating process. This pocket is similar in most strains of rhinoviruses and [[enterovirus]]es, which can cause diarrhea, [[meningitis]], [[conjunctivitis]], and [[encephalitis]].<ref>{{cite journal |title=Activity of Pleconaril against Enteroviruses |author1=Daniel C. Pevear |author2=Tina M. Tull |author3= Martin E. Seipel |journal=Antimicrobial Agents and Chemotherapy |year=1999|volume=43 |issue=9 |pages=2109–2115 |doi=10.1128/AAC.43.9.2109 |pmid=10471549 |pmc=89431 }}</ref>

Some scientists are making the case that a vaccine against rhinoviruses, the predominant cause of the common cold, is achievable.
Vaccines that combine dozens of varieties of rhinovirus at once are effective in stimulating antiviral antibodies in mice and monkeys, researchers reported in ''[[Nature Communications]]'' in 2016.<ref>{{cite news |url=https://www.nature.com/articles/ncomms12838 |author1=Lee, S. |author2=Nguyen, M. |author3=Currier, M. |title=A polyvalent inactivated rhinovirus vaccine is broadly immunogenic in rhesus macaques |publisher=Nature Communications |year=2016}}</ref>

Rhinoviruses are the most common cause of the common cold; other viruses such as [[respiratory syncytial virus]], [[parainfluenza virus]] and [[adenoviruses]] can cause them too.<ref>{{cite web |url=https://bready.blog.ranftl.org/health/common-cold-causes |title=Common Cold Causes: Rhinoviruses and More |access-date=8 January 2022 |archive-date=8 January 2022 |archive-url=https://web.archive.org/web/20220108160711/https://bready.blog.ranftl.org/health/common-cold-causes |url-status=dead }}</ref> Rhinoviruses also exacerbate asthma attacks. Although rhinoviruses come in many varieties, they do not drift to the same degree that influenza viruses do. A mixture of 50 inactivated rhinovirus types should be able to stimulate neutralizing antibodies against all of them to some degree.<ref>{{cite web |url=https://grantome.com/grant/NIH/R43-AI131750-01 |title=Development of polyvalent inactivated rhinovirus vaccine |year=2017|last1=Tang |first1=Roderick |last2=Moore |first2=Martin }}</ref>

====During viral synthesis====
A second approach is to target the processes that synthesize virus components after a virus invades a cell.

=====Reverse transcription=====
One way of doing this is to develop [[nucleotide]] or [[nucleoside]] analogues that look like the building blocks of [[RNA]] or [[DNA]], but deactivate the enzymes that synthesize the RNA or DNA once the analogue is incorporated. This approach is more commonly associated with the inhibition of [[reverse transcriptase]] (RNA to DNA) than with "normal" transcriptase (DNA to RNA).

The first successful antiviral, [[aciclovir]], is a nucleoside analogue, and is effective against herpesvirus infections. The first antiviral drug to be approved for treating HIV, [[zidovudine]] (AZT), is also a nucleoside analogue.

An improved knowledge of the action of reverse transcriptase has led to better nucleoside analogues to treat HIV infections. One of these drugs, [[lamivudine]], has been approved to treat hepatitis B, which uses reverse transcriptase as part of its replication process. Researchers have gone further and developed inhibitors that do not look like nucleosides, but can still block reverse transcriptase.

Another target being considered for HIV antivirals include [[RNase H]]—which is a component of reverse transcriptase that splits the synthesized DNA from the original viral RNA.

=====Integrase=====
Another target is [[integrase]], which integrate the synthesized DNA into the host cell genome. Examples of integrase inhibitors include [[raltegravir]], [[elvitegravir]], and [[dolutegravir]].

=====Transcription=====
Once a virus genome becomes operational in a host cell, it then generates [[messenger RNA]] (mRNA) molecules that direct the synthesis of viral proteins. Production of mRNA is initiated by proteins known as [[transcription factor]]s. Several antivirals are now being designed to block attachment of transcription factors to viral DNA.

=====Translation/antisense=====
Genomics has not only helped find targets for many antivirals, it has provided the basis for an entirely new type of drug, based on "antisense" molecules. These are segments of DNA or RNA that are designed as complementary molecule to critical sections of viral genomes, and the binding of these antisense segments to these target sections blocks the operation of those genomes. A phosphorothioate antisense drug named [[fomivirsen]] has been introduced, used to treat opportunistic eye infections in AIDS patients caused by [[cytomegalovirus]], and other antisense antivirals are in development. An antisense structural type that has proven especially valuable in research is [[morpholino]] antisense.

Morpholino oligos have been used to experimentally suppress many viral types:
* [[calicivirus]]es<ref name="pmid11763348">{{cite journal |vauthors=Stein DA, Skilling DE, Iversen PL, Smith AW |title=Inhibition of Vesivirus infections in mammalian tissue culture with antisense morpholino oligomers |journal=Antisense Nucleic Acid Drug Dev |volume=11 |issue=5 |pages=317–25 |year=2001|pmid=11763348 |doi=10.1089/108729001753231696}}</ref>
* [[flavivirus]]es (including [[West Nile virus]])<ref name="pmid15795246">{{Cite journal | last1 = Deas | first1 = T. S. | last2 = Binduga-Gajewska | first2 = I. | last3 = Tilgner | first3 = M. | last4 = Ren | first4 = P. | last5 = Stein | first5 = D. A. | last6 = Moulton | first6 = H. M. | last7 = Iversen | first7 = P. L. | last8 = Kauffman | first8 = E. B. | last9 = Kramer | first9 = L. D. | last10 = Shi | first10 = P. -Y. | doi = 10.1128/JVI.79.8.4599-4609.2005 | title = Inhibition of Flavivirus Infections by Antisense Oligomers Specifically Suppressing Viral Translation and RNA Replication | journal = Journal of Virology | volume = 79 | issue = 8 | pages = 4599–4609 | year = 2005 | pmid = 15795246| pmc =1069577 }}</ref>
* [[dengue]]<ref name="pmid15795296">{{cite journal |title=Inhibition of Dengue Virus Serotypes 1 to 4 in Vero Cell Cultures with Morpholino Oligomers |journal=J. Virol. |volume=79 |issue=8 |pages=5116–28 |year=2005|pmid=15795296 |pmc=1069583 |doi=10.1128/JVI.79.8.5116-5128.2005 |last1=Kinney |first1=R. M. |last2=Huang |first2=C. Y.-H. |last3=Rose |first3=B. C. |last4=Kroeker |first4=A. D. |last5=Dreher |first5=T. W. |last6=Iversen |first6=P. L. |last7=Stein |first7=D. A.}}</ref>
* [[Hepatitis C virus|HCV]]<ref name="pmid12883495">{{cite journal |vauthors=McCaffrey AP, Meuse L, Karimi M, Contag CH, Kay MA |s2cid=1612244 |title=A potent and specific morpholino antisense inhibitor of hepatitis C translation in mice |journal=Hepatology |volume=38 |issue=2 |pages=503–08 |year=2003 |pmid=12883495 |doi=10.1053/jhep.2003.50330|doi-access=free }}</ref>
* [[coronavirus]]es<ref name="pmid15140987">{{cite journal |title=Antisense Morpholino-Oligomers Directed against the 5' End of the Genome Inhibit Coronavirus Proliferation and Growth† |journal=J. Virol. |volume=78 |issue=11 |pages=5891–99 |date=June 2004 |pmid=15140987 |pmc=415795 |doi=10.1128/JVI.78.11.5891-5899.2004 |last1=Neuman |first1=B. W. |last2=Stein |first2=D. A. |last3=Kroeker |first3=A. D. |last4=Paulino |first4=A. D. |last5=Moulton |first5=H. M. |last6=Iversen |first6=P. L. |last7=Buchmeier |first7=M. J.}}</ref>

=====Translation/ribozymes=====
Yet another antiviral technique inspired by genomics is a set of drugs based on [[ribozyme]]s, which are enzymes that will cut apart viral RNA or DNA at selected sites. In their natural course, ribozymes are used as part of the viral manufacturing sequence, but these synthetic ribozymes are designed to cut RNA and DNA at sites that will disable them.

A ribozyme antiviral to deal with [[hepatitis C]] has been suggested,<ref name="pmid14659071">{{cite journal |vauthors=Ryu KJ, Lee SW |title=Identification of the most accessible sites to ribozymes on the hepatitis C virus internal ribosome entry site |journal=J. Biochem. Mol. Biol. |volume=36 |issue=6 |pages=538–44 |year=2003 |pmid=14659071 |doi= 10.5483/BMBRep.2003.36.6.538|doi-access=free }}</ref> and ribozyme antivirals are being developed to deal with HIV.<ref name="pmid11282007">{{cite journal |vauthors=Bai J, Rossi J, Akkina R |title=Multivalent anti-CCR ribozymes for stem cell-based HIV type 1 gene therapy |journal=AIDS Res. Hum. Retroviruses |volume=17 |issue=5 |pages=385–99 |date=March 2001 |pmid=11282007 |doi=10.1089/088922201750102427}}</ref> An interesting variation of this idea is the use of genetically modified cells that can produce custom-tailored ribozymes. This is part of a broader effort to create genetically modified cells that can be injected into a host to attack pathogens by generating specialized proteins that block viral replication at various phases of the viral life cycle.

=====Protein processing and targeting=====
Interference with post translational modifications or with targeting of viral proteins in the cell is also possible.<ref>{{cite journal |vauthors=Alarcón B, González ME, Carrasco L | year = 1988 | title = Megalomycin C, a macrolide antibiotic that blocks protein glycosylation and shows antiviral activity | journal = FEBS Lett | volume = 231 | issue = 1| pages = 207–11 | pmid = 2834223 | doi=10.1016/0014-5793(88)80732-4| s2cid = 43114821 | doi-access = free | bibcode = 1988FEBSL.231..207A }}</ref>

====Protease inhibitors====
Some viruses include an enzyme known as a [[protease]] that cuts viral protein chains apart so they can be assembled into their final configuration. HIV includes a protease, and so considerable research has been performed to find "[[protease inhibitor (pharmacology)|protease inhibitors]]" to attack HIV at that phase of its life cycle.<ref>{{Cite book |vauthors=Anderson J, Schiffer C, Lee SK, Swanstrom R |chapter=Viral Protease Inhibitors |title=Antiviral Strategies |volume= 189|issue=<!-- --> |pages=85–110 |year=2009 |pmid=19048198 |doi=10.1007/978-3-540-79086-0_4 |series=Handbook of Experimental Pharmacology |pmc=7120715 |isbn=978-3-540-79085-3}}</ref> Protease inhibitors became available in the 1990s and have proven effective, though they can have unusual side effects, for example causing fat to build up in unusual places.<ref>{{cite journal |title=The Role of Protease Inhibitors in the Pathogenesis of HIV-Associated Lipodystrophy: Cellular Mechanisms and Clinical Implications |journal=Toxicol Pathol |volume=37 |issue=1 |pages=65–77 |year=2009 |pmid=19171928 |doi=10.1177/0192623308327119 |pmc=3170409 |last1=Flint |first1=O. P. |last2=Noor |first2=M. A. |last3=Hruz |first3=P. W. |last4=Hylemon |first4=P. B. |last5=Yarasheski |first5=K. |last6=Kotler |first6=D. P. |last7=Parker |first7=R. A. |last8=Bellamine |first8=A.}}</ref> Improved protease inhibitors are now in development.

Protease inhibitors have also been seen in nature. A protease inhibitor was isolated from the [[shiitake]] mushroom (''Lentinus edodes'').<ref name="pmid10411656">{{cite journal |vauthors=Odani S, Tominaga K, Kondou S |title=The inhibitory properties and primary structure of a novel serine proteinase inhibitor from the fruiting body of the basidiomycete, Lentinus edodes |journal=European Journal of Biochemistry |volume=262 |issue=3 |pages=915–23 |year=1999 |pmid=10411656 |doi=10.1046/j.1432-1327.1999.00463.x|doi-access=free }}</ref> The presence of this may explain the Shiitake mushrooms' noted antiviral activity ''in vitro''.<ref name="pmid2469420">{{cite journal |vauthors=Suzuki H, Okubo A, Yamazaki S, Suzuki K, Mitsuya H, Toda S |title=Inhibition of the infectivity and cytopathic effect of human immunodeficiency virus by water-soluble lignin in an extract of the culture medium of Lentinus edodes mycelia (LEM) |journal=Biochemical and Biophysical Research Communications |volume=160 |issue=1 |pages=367–73 |year=1989 |pmid=2469420 |doi=10.1016/0006-291X(89)91665-3}}</ref>

=====Long dsRNA helix targeting=====
Most viruses produce long [[dsRNA]] helices during transcription and replication. In contrast, uninfected [[mammalian]] cells generally produce dsRNA helices of fewer than 24 [[base pairs]] during transcription. '''[[DRACO]]''' ([[RNA#Double-stranded RNA|double-stranded RNA]] activated caspase [[oligomer]]izer) is a group of experimental antiviral drugs initially developed at the [[Massachusetts Institute of Technology]]. In cell culture, DRACO was reported to have broad-spectrum efficacy against many infectious viruses, including [[Dengue virus|dengue flavivirus]], Amapari and Tacaribe [[arenavirus]], Guama [[Bunyaviridae|bunyavirus]], [[H1N1 influenza]] and [[rhinovirus]], and was additionally found effective against influenza ''in vivo'' in weanling mice. It was reported to induce rapid [[apoptosis]] selectively in virus-infected mammalian cells, while leaving uninfected cells unharmed.<ref>{{cite journal| pmc=3144912 | pmid=21818340 | doi=10.1371/journal.pone.0022572 | volume=6 | title=Broad-spectrum antiviral therapeutics | year=2011 |vauthors=Rider TH, Zook CE, Boettcher TL, Wick ST, Pancoast JS, Zusman BD | journal=PLOS ONE | issue=7 | page=e22572 | bibcode=2011PLoSO...622572R| doi-access=free }}</ref> DRACO effects cell death via one of the last steps in the apoptosis pathway in which complexes containing intracellular apoptosis signalling molecules simultaneously bind multiple [[Caspase|procaspases]]. The procaspases transactivate via cleavage, activate additional [[caspase]]s in the cascade, and cleave a variety of cellular proteins, thereby killing the cell.{{citation needed|date=September 2022}}

====Assembly====
[[Rifampicin]] acts at the assembly phase.<ref name="pmid8289340">{{cite journal |author1=Sodeik B |author2= Griffiths G |author3= Ericsson M |author4= Moss B |author5= Doms RW |title=Assembly of vaccinia virus: effects of rifampin on the intracellular distribution of viral protein p65 |journal=J. Virol. |volume=68 |issue=2 |pages=1103–14 |year=1994 |pmid=8289340 |pmc=236549|doi=10.1128/JVI.68.2.1103-1114.1994|author1-link= Beate Sodeik }}</ref>

====Release phase====
The final stage in the life cycle of a virus is the release of completed viruses from the host cell, and this step has also been targeted by antiviral drug developers. Two drugs named [[zanamivir]] (Relenza) and [[oseltamivir]] (Tamiflu) that have been recently introduced to treat influenza prevent the release of viral particles by blocking a molecule named [[neuraminidase]] that is found on the surface of flu viruses, and also seems to be constant across a wide range of flu strains.