How Are New Antivirals Discovered

To the present day our antivirals have been found by true Pasteurian logic, to be paraphrased as 'discovery favours with prepared mind'. In practical laboratory terms 'off-the-shelf chemicals are subjected to a biological screen. A virus-susceptible cell line is incubated with a non-toxic concentration of novel drug and the 'target' or 'challenge' virus is then added. If the cell is rendered uninfectable or if there is a 10-100-fold reduction in the quantity of virions produced by the drug-treated cell, the drug is further investigated. The many stages of the lifecycle of a virus give chemotherapeutists the opportunity to design or find compounds which interrupt virion binding, penetration or more usually some vital step dependent upon a unique viral enzyme such as RNA polymerase, protease or integrase (Table 4.2). Virologists have screened through libraries of millions of already synthesized compounds, either using biological or, increasingly, automated ELISA screens against particular viral

Table 4.2 STEPS IN VIRUS REPLICATION THAT ARE SUSCEPTIBLE TO INHIBITORS

Target

Antiviral

Virus/infection

(1) Virus adsorption

Dextran sulphate CD4 (receptor)

HIV-1 HIV-1

(2) Viral penetration and uncoating

Amantadine (Symmetrel or Lysovir)* Rimantadine* gp41 peptides (fusion)

Influenza A HIV-1

(3) Virus-induced enzymes Reverse transcriptase

DNA polymerase

Zidovudine (AZT) Zalcitabine (ddC) Didanosine (ddl) Stavudine (D4T) Lamivudine (3TC) Delavirdine Nevirapine Efavirenz Aciclovir (ACV)* Penciclovir*

HIV-1

Generalized herpes and shingles infections and genital HSV infections

Trifluorothymidine* (TFT)

Cytomegalovirus infections (e.g. pneumonia) Eye infections with HSV

Cidofovir

Saquinavir*

Indinavir*

Nefinavir*

Ritonavir*

CMV infections Pox viruses HIV

Neuraminidase

Zanamivir* Oseltamivir*

Influenza A and B

Viral protein synthesis

Interferon*

Many viruses

Free virus particle

Pleconaril

Rhinoviruses

  • A licensed antiviral.
  • A licensed antiviral.

proteins. Once a molecule binding to a viral protein has been located, a more efficient molecule can be 'designed' by the chemists. Excellent examples of semi-designed antivirals are inhibitors of the common cold virus, which bind tightly to the viral capsid protein and which can be visualized by X-ray crystallography in the binding pocket on the virion surface, and also inhibitors of the influenzavirus neuraminidase enzyme. In the latter case the enzyme-active site had been identified as a saucer-like depression on the top of the viral neuraminidase protein and X-ray crystallography identified exactly which amino acids of the viral protein were interacting with an inhibitor. Chemists have modified an already discovered drug by addition of a single side chain to enable it to bind more strongly to the influenza neuraminidase protein and hence cause stronger inhibition of viral replication. The effects occur at a late stage of viral growth where the function of the neuraminidase is to cause release of newly synthesized virus from the infected cell.

But, do not forget that the members of the plant kingdom are excellent chemists as well and laboratories are intensifying the search to discover novel molecules in plant extracts which, by chance, inhibit viruses. There is a strong history here to remember, with A. Fleming's discovery of the penicillin antibiotic, synthesized by a penicillium mould on an orange.

Chemists also believe that thousands of nucleoside analogues remain to be synthesized and tested as antivirals. Alternatively, these compounds may already be in existence and on the shelf as part of a completely unrelated biological screening programme. The now classic anti-herpes nucleoside analogue aciclovir was initially synthesized as an anti-cancer drug. Aciclovir is structurally related to the natural nucleoside 2' deoxyguanosine but has a disrupted sugar ring (acyclic). Nucleoside analogues are some of our most powerful antivirals and even more surprisingly some, like aciclovir, appear to

Table 4.3 RELATIVELY FEW POINT MUTATIONS IN VIRAL GENES CAN LEAD TO DRUG RESISTANCE

Virus

Drug

Specific mutations responsible for resistance

Influenza A

Amantadine, zanamivir

Mutations in M2 gene

and oseltamivir

(amantadine) and possibly in HA gene and NA genes (oseltamivir and zanamivir). Fortunately NA mutants are less able to spread

Herpes simplex

Aciclovir

Mutations in the viral DNA polymerase or TK enzyme. Importantly, some viruses without thymidine kinase or possessing an altered TK may be less virulent in vivo and so will not spread

HIV-1

Zidovudine and other

Five mutations in the

dideoxynucleoside

reverse transcriptase gene

analogues

Protease inhibitors

Mutations in the HIV protease

be extraordinarily safe in the clinic and, not surprisingly, have become the virologists' favourite molecule.

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