Mini-reviewRational design of polymerase inhibitors as antiviral drugs
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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2016, Antiviral ResearchCitation Excerpt :A nucleoside or nucleotide analog will be first converted to the triphosphorylated form by host or viral enzymes, and then compete with the natural nucleoside triphosphates as a chain terminator of the growing viral genome (Lou et al., 2014). Both the efficiency of conversion to the triphosphorylated form and the blockage of viral genome elongation are selective and determine the inhibitory activity (Oberg, 2006). NITD008 was reported to selectively inhibit viruses within the Flaviviridae family, including Dengue virus, West Nile virus, yellow fever virus, or EV71, both in vitro and in vivo (Deng et al., 2014; Shang et al., 2014; Yin et al., 2009), but did not show antiviral activity to Western equine encephalitis virus or vesicular stomatitis virus (Yin et al., 2009).
RacGTPase-activating protein 1 interacts with hepatitis C virus polymerase NS5B to regulate viral replication
2014, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Allosteric modulators or regulators targeting viral or host proteins have become an emerging topic of interest because they offer high selectivity and competitive advantages over most classic drugs, which were designed to target orthosteric (active) sites [26]. This has been applied to rational design for HCV NS5B inhibitors [27]. Thus the inhibitors against RacGAP1 might be combined with allosteric drugs to achieve a more potent inhibition against NS5B to combat HCV.
An H-phosphonate strategy for the synthesis of 2′,3′- dideoxynucleoside triphosphates and homodinucleotides
2014, Chinese Chemical LettersCitation Excerpt :In the host cells, the transformation of ddNs into the 5′-triphosphate form is essential for their integration into viral DNA as chain terminators [2]. Therefore, ddN 5′-triphosphates have always been important synthetic targets for the investigation of the antiviral mechanisms of the parent ddNs [3]. AZT 5′-triphosphate (AZTTP) and d4T 5′-triphosphate (d4TTP) have been prepared via the conventional “one-pot, three-step” [4] and salicyl chlorophosphite (SCP) methods in low to moderate yields [5].
Current progress in antiviral strategies
2014, Trends in Pharmacological Sciences