The rational design of antiviral compounds

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Compare to the antibiotic therapy available for bacterial infections, antiviral chemotherapy is still in its infancy. There are still many viral diseases for which no effective drugs or vaccines exist. Unlike most bacterial which leads an independent existence outside host cells, viruses are intracellular parasites which requires host cell mechanisms in order to replicate. It has proved difficult to find compounds that can selectively block viral replication without interference to the normal cellular processes and thus with significant toxicity to the host.

Some antiviral compounds like amantadine were discovered by simple screening for activity against influenza or other viruses. A more rational approach would be to focus on developing compounds which inhibit the replication of the virus at a specific step in its life cycle. This approach requires detailed knowledge of the mechanism of replication for that particular virus. Many antiviral agents in clinical use today or undergoing active evaluation are synthetic chemical analogues of nucleosides. Because of their close chemical similarity to naturally occurring analogues or substrates, they may be falsely incorporated in the viral biosynthetic process, thereby disrupting viral replication.

To date. the best antiviral compound available is acyclovir. It is highly selective against herpes simplex virus, and to a lesser extent against other members of the herpes virus family, with minimal toxicity for the host. Its selectivity is based on the fact that it is taken up by cells that contain HSV thymidine kinase in order to be converted into its active form, acyclovir triphosphate. Acyclovir triphoshate act both as a substrate and inhibitor of viral DNA polymerase. Acyclovir serves as a good model for the future development of antiviral agent.

There are two possible rational approaches which could be used in the design of antiviral compounds;-

1. Modification of existing antiviral compounds

2. Design of new antiviral compounds directed at specific steps in the replication cycle of particular viruses

Modification of existing compounds

With this approach, analogues to an existing antiviral compound are synthesized in the hope of obtaining a compound with one or desired characteristics. eg. better oral bioavailability, better CNS bioavailability, lesser side effects, more potent antiviral effects against a virus of the same family, and less likelihood of developing resistance. This approach was used to produce rimatadine, which is a close relative of amantadine but with fewer side effects. This approach was also used in the case of acyclovir in the hope of finding compounds with better oral bioavailability or better activity against VZV, CMV and EBV. Valicyclovir is a prodrug of acyclovir, after oral administration. 63% of the drug is excreted as acylcovir in the urine of laboratory animals. This is a 200 - 400% improvement on acyclovir given orally.

Purposefully designed antiviral compounds

This is increasingly becoming the method of choice in the development of new anti-viral agent. By targeting a well-defined specific target of the virus, it is hoped that the agent would be more potent and specific at the same time, thus producing less side effects. The viral targets that are chosen are involved in one or more specific steps of replication. Using this approach, a number of effective antiviral agents had been developed e.g.. influenza neuraminidase inhibitors, HIV protease and fusion inhibitors.

1. HIV

HIV is the target of unprecedented antiviral research at present, and the results had been spectacular. Within about a decade, HIV infection had gone from a "death sentence" to a disease that can be controlled indefinitely. A large number of anti-HIV agents had been developed, some of them purposefully. Several steps in its replicative process had been targeted for specifically designed compounds, examples include;-

a. Reverse transcriptase (RT) - this is the target which has attracted the most attention thus far. Many drugs had been developed which block the function of this enzyme.

Nucleoside Reverse RT Inhibitor - AZT, ddI, ddA, ddC,
Non-nucleoside RT inhibitors - Nevirapin and Efavirenz

b HIV protease - To date, the most potent anit-HIV agents are HIV-protease inhibitors. Examples of these include Ritonavir and Saquinavir. Proteolytic action is required in order to cleave the HIV fusion gag-pol protein into individual proteins and this proved to be a good target for custom-designed compounds.

c. Entry of virus

Enfuvirtide works by disrupting the HIV-1 molecular machinery at the final stage of fusion with the target cell, preventing uninfected cells from becoming infected.
Maraviroc is an entry inhibitor which blocks the chemokine receptor CCR5 which HIV uses as a coreceptor to bind and enter a human helper T cell. Because HIV can also use another coreceptor, CXCR4, an HIV tropism test such as a trofile assay must be performed to determine if the drug will be effective.

d. Other targets - other targets involved in HIV-replication are being researched at present, including the CD4 molecule that is used for attachments, HIV tat, and those that are involved in glycosylation, viral mRNA translation, and ribosomal frame shifting. Without doubt, more and more effective anti-HIV agents will be available in future that is based on rational design against a particular HIV-specific target.

2. Influenza A

The rational approach to drug design has led to the design of several potent inhibitors of influenza neuraminidase of which two, zanamivir (Relenza) and oseltamivir (Tamiflu) are licensed for the treatment of influenza A and B infections. In clinical trials, both agents have demonstrated efficacy with minimal side effects. Because of its poor bioavailibility, Zanamivir must be given by inhalation whilst oseltamivir can be given orally. Because selection of drug-resistant mutants characterized by changes in NA requires prolonged passage in tissue culture, development of zanamivir and oseltamivir-resistant viruses is not expected to occur readily in patients. The available information suggests that mutants may be less stable in vivo. In addition to treatment, oseltamivir is also licensed for prophylaxis and has become the drug of choice for treating influenza A infection in lieu of Amantidine, against which resistant strains developed quickly.

Other Viruses

Fomivirsen is an ant-sense oligonucleotide that blocks translation of CMV mRNA. It is licensed for the treatment of CMV retinitis in immunocompromised individuals. The "WIN" compounds inhibit the uncoating of picornaviruses by fitting into the pockets on the floor of the canyons, thus increasing the stability of the virus and hence preventing uncoating. The size of the "WIN" compounds may be adjusted to obtain the best fit. However, no WIN compounds are yet licensed for treatment to date. There is intense ongoing research on developing specific anti-viral agents through rational for other viruses, notably other herpesviruses and hepatitis viruses.

It is clear that a detailed understanding of the molecular targets encoded by viruses can be of potential use in the development of specific antiviral therapy. Potent antiviral therapy is now available against several viral diseases through this approach for HIV and influenza A viruses. More and better agents will certainly will available in the near future.