Elsevier

Antiviral Research

Volume 71, Issues 2–3, September 2006, Pages 90-95
Antiviral Research

Mini-review
Rational design of polymerase inhibitors as antiviral drugs

Dedicated to Prof. Erik De Clercq on the occasion of reaching the status of Emeritus-Professor at the Katholieke Universiteit Leuven in September 2006.
https://doi.org/10.1016/j.antiviral.2006.05.012Get rights and content

Abstract

Almost all viruses have polymerases which are suitable targets for antiviral drugs. The development of selective polymerase inhibitors started with screening of compounds in virus-infected cell cultures and the mechanism of action was investigated once an inhibitor had been found. Especially nucleoside analogs were screened as their triphosphates were potential substrates for polymerases. However, the stepwise phosphorylation by cellular, and sometimes viral, kinases to the active triphosphate prevented a truly rational design of polymerase inhibitors.

Nucleotide analogs offers a type of compounds which could be designed in a more rational way than nucleoside analogs since the first, most selective, phosphorylation step is eliminated in the path to the active inhibitor.

The development of pyrophosphate analogs made rational design possible since these compounds act directly on the viral enzyme, but the room for structural variation was limited.

The non-nucleoside HIV reverse transcriptase inhibitors are direct inhibitors and can thus be designed in a truly rational way by use of structure information on the enzyme-inhibitor complex by use of X-ray and NMR. This rational design of allosteric inhibitors is also being used in the development of inhibitors to other viral polymerases.

Introduction

The possibility to design antiviral drugs in a rational way and to selectively direct them against a viral function became possible by the discovery of virus-coded enzymes. The first viral enzyme to be reported was a viral polymerase, poxvirus DNA dependant RNA polymerase (Kates and McAuslan, 1967). Before that time the search for antiviral drugs was based on random screening.

Today many viral enzymes, especially polymerases and proteases, are used in the rational design of selective inhibitors and known to be excellent targets for antiviral drugs. Some aspects on the rational design of polymerase inhibitors as antiviral drugs will be discussed.

Section snippets

Rational design of an enzyme inhibitor and rational design of a drug

Even if obvious to most researchers it might be worth pointing out the difference between the design of an enzyme inhibitor and the design of a drug intended for clinical use. Today a viral polymerase can be cloned, expressed and analyzed by X-ray, NMR and other methods to determine the structure and the exact binding of substrates, template and inhibitors. These tools to analyze the active site as well as knowledge about substrates and reaction products greatly facilitate the rational design

Types of polymerase inhibitors

Three types of polymerase inhibitors are recognized; substrate analogs (nucleoside and nucleotide analogs), product analogs (pyrophosphate analogs) and allosteric inhibitors (non-nucleoside reverse transcriptase inhibitors, NNRTIs). The possibility of rational design differs for these types as will be discussed. The resistance mutations are also different which makes combinations of polymerase inhibitors useful in reducing the rate of resistance development. Compounds intercalating or otherwise

Development of nucleoside analogs as polymerase inhibitors

Many of the first antiviral drugs were nucleoside analogs. They were discovered by screening and serendipity aided by the efforts of many clever nucleoside chemists precariously guided by the inhibition of virus replication in cell culture. These efficacy results from cell cultures were of rather limited use for the medicinal chemist in designing the next compound to synthesize, since the mechanism of action was unclear in the beginning, and if it was due to an inhibition of a viral polymerase,

Development of nucleotide analogs as polymerase inhibitors

The use of monophosphate nucleotide analogs (nucleoside phosphonates) as polymerase inhibitors avoids an important hurdle, the first phosphorylation step needed for activation to a “triphosphate”, and thus facilitates rational design (De Clercq et al., 1986). Structure–activity relations can be better analyzed for nucleotide than nucleoside analogs and cell culture assays for inhibition of viral replication more directly reflect inhibition of a viral polymerase. As seen in Table 1 there are

Development of pyrophosphate analogs as polymerase inhibitors

A simple byproduct of a polymerase reaction is pyrophosphate and analogs to pyrophosphate have been designed and evaluated as polymerase inhibitors (for review see Öberg, 1989). This evaluation was facilitated by the inhibitors direct action not involving any metabolic transformations and structure–activity relations could be established for various polymerases. Influenza virus RNA polymerase was initially found to be inhibited both by pyrophosphate (not surprising) and oxalic acid. Combining

Development of allosteric polymerase inhibitors

With the allosteric polymerase inhibitors of HIV RT, the non-nucleoside reverse transcriptase inhibitors (NNRTIs), development of antiviral polymerase inhibitors has reached a stage where one could truly talk about rational design of polymerase inhibitors.

Screening of compound libraries against HIV RT rapidly resulted in several structurally different inhibitors as excellent starting points for rational design of potent and selective inhibitors (Miyasaka et al., 1989, Pauwels et al., 1990,

Conclusions

Antiviral inhibitors can now be designed in a rational way whether they are polymerase or protease inhibitors or belong to some other type of enzyme inhibitors. However, the task to make a useful drug is complex since antiviral potency is only one of several parameters which have to be optimized in parallel. University researchers will typically not have all the resources to provide compounds ready to be assigned candidate drug status but rather to provide new ideas and lead compounds which

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