Viruses uncoating

Inhibitors that bind to free virus particles have been little investigated in the past with the notable exception of rhinoviruses, where a number of quite potent molecules bind to the external protein of the virus and hence inhibit latter stages of virus uncoating. Possibly the only compound known at present, apart from disinfectants, that could affect the virus stability is A1-721, a mixture of neutral... 

The genome in influenza A and B types is enclosed within an outer lipoprotein envelope (Fig. 17.1). The Ml protein lines the inside of the envelope and is chemically bound to the ribonucleoprotein [14], The Ml protein plays an important role in the mediation of nuclear export of viral ribonucleoproteins and also in virus assembly and budding during the infectious cycle [5, 14, 15], An antigenic protein M2, which functions as a proton-selective ion channel, is present in the viral membrane of influenza A viruses [6, 13], In influenza B, the ion channel activity to aid virus uncoating in the endosome is carried out by the similar integral membrane protein BM2 [11],... 

Amantadine is a symmetrical CIO tricyclic amine with an unusual structure (1-adamantanamine hydrochloride). It interferes with virus uncoating (1) by blocking the M2 ion channel, which is needed to affect a pH change that helps to initiate the uncoating process. Most consistent antiviral activity has been observed against influenza A virus, but amantadine has httle or no activity against influenza B virus (2). However, influenza A virus can become rapidly resistant to amantadine in vitro (3). Amantadine also promotes the release of dopamine from nerve endings, but may also delay its reuptake into synaptic vesicles. 

Bukrinskaya AG, Vorkunova NK, Narmanbetova RA. Rimantadine hydrochloride blocks the second step of influenza virus uncoating. Arch Virol 1980 66(3) 275-82. 

Rimantadine hydrochloride (a-methyl-1-adamantanemethylamine hydrochloride) is a synthetic adamatane derivative that is structurally and pharmacologically related to amantadine (21,22). It appears to be more effective than amantadine hydrochloride against influenza A, with fewer CNS side effects. Rimantadine hydrochloride is thought to interfere with virus uncoating by inhibiting the release of specific proteins. It may act by inhibiting RT or the synthesis of virus-specific RNA, but it does not inhibit virus adsorption or penetration. It appears to produce a virustatic effect early in the virus replication. It is used widely in Russia and Europe. 

A rather distantly related analogue incorporating a 3-di-carbonyl moiety as a bioisosteric replacement for a carboxyl, aril done (55), blocks the uncoating of polio virus and herpes simplex virus type I and thus inhibits infection of cells and l.he early stages of virus replication. Thus effective therapy would require careful timing as it does with amantidine. 

Virus adsorption, entry and uncoating. Drug Disc Today 1 316-324 MeanweU NA, Krystal M (1996b) Taking aim at a moving target - inhibitors of influenza virus. II. 

In general terms, four main stages can be recognized in the multiplication of human viruses, (i) attachment (ii) penetration and uncoating (iii) production of viral proteins and replication of viral nucleic acid, (iv) assembly and release of progeny viruses. 

De Clercq E, Yamamoto N, Pauwels R, Baba M, Schols D, Nakashima H, Balzarini J, Debyser Z, Murrer BA, Schwartz D, Thornton D, Bridger G, Fricker S, Henson G, Abrams M, Picker D. Potent and selective inhibition of human immunodeficiency virus (HIV)-l and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event. Proc Natl Acad Sci USA 1992 89 5286-5290. 

Penetration. After fusion of viral and host membranes, or uptake into a phagosome, the virus particle is carried into the cytoplasm across the plasma membrane. This penetration process is an active one that requires expenditure of energy by the cell. At this stage the envelope and the capsid are shed, and the viral nucleic acids are released. The uncoating of virus accounts for the drop in infectious virus assayed, because the uncoated virus cannot withstand the assay conditions. 

Following the process of virus attachment, penetration, and uncoating described before, the retrovirus undergoes replication. 

Amantadine (C) specifically affects the replication of influenza A (RNA) viruses, the causative agent of true influenza. These viruses are endocytosed into the cell. Release of viral DNA requires protons from the acidic content of endosomes to penetrate the virus. Presumably, amantadine blocks a channel protein in the viral coat that permits influx of protons thus, uncoating is prevented. Moreover, amantadine inhibits viral maturation. The drug is also used prophylactically and, if possible, must be taken before the outoreak of symptoms. It also is an antiparkinsonian... 

Amantadine (see Chapter 21, Section Ill.b.l) is a tricyclic symmetric adamantanamine. It inhibits the uncoating stage which takes place for binding of the virus to cells, of the influenza-A virus. It is used prophylactically for influenza-A infection, and when given within 24 hours of onset for active influenza-A. It shows good oral absorption and is excreted in the urine with an elimination half-life of about 12 hours. The adverse effects are mainly on the CNS and include insomnia, restlessness, nervousness and depression. 

Although the specific details of replication vary among types of viruses, the overall process can be described as consisting of five phases (1) attachment and penetration, (2) uncoating, (3) synthesis of viral components, (4) assembly of virus particles, and (5) release of the... 

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