Platform approach

During the work on ATP-competitive inhibitors for kinases, it became evident that there were strong synergies in assays, medicinal chemistry, drug design etc.

between different kinase projects and that it would be advantageous to attack the many drug targets in this class in a coordinated fashion (ter Haar et al 2004). As a consequence directed compound collections were created, which represented likely inhibitor scaffold. At the same time structural biology was emphasized, so that the interactions of any compound with the target compounds could be rapidly analysed, and structure—activity relationships would emerge. In addition a large panel of assays was set up to examine the selectivity of any emerging compound.

Such synergies clearly exist for flaviviral diseases. While it is currently unclear whether it will be possible to create drugs that have antiviral activity against several flaviviruses or whether different chemical entities are needed for dengue and for example Japanese encephalitis, there is no question that synergies especially in molecular biology, biochemistry and chemistry can be exploited to attack several of these viral diseases. NITD is following this avenue in all of our drug discovery efforts.

Target product profile

At the start of a drug discovery effort for any disease, it is important to consider the need of a potential patient. In dengue we have at least two potential points of intervention as shown in Fig. 1: an antiviral drug that would be used to reduce the viral load in the early stages of the disease or a modulator of host targets that would prevent or treat dengue haemorrhagic fever (DHF). Both approaches have potential challenges and pitfalls. While the effective window of opportunity for using an antiviral drug may be short, designing an immune-modulator poses the difficult

Mosquito Bite

Reduce viral load Target: Virus i

Mosquito Bite

Reduce viral load Target: Virus

2-10 days

3-4 days

Slow Recovery

Prevent or treat DHF Target: Host Factors

FIG. 1. Potential intervention strategy for dengue antivirals or modulators of host targets.

challenge of finding a treatment without unwanted side effects or toxicity. This latter problem is not made easier by our lack of detailed understanding of the pathogenesis profile of the disease and the absence of a disease model.

NITD has decided to initially focus on an antiviral drug whose target product profile is shown in Table 1. Since dengue epidemics occur mainly in developing countries, a cheap oral drug that neither induces nor inhibits liver enzymes and that can be given once a day would be ideal.

The influence of a drug on the cytochrome P450 enzymes is a very important consideration for flaviviral infections as rural patients in tropical countries often are afflicted with other diseases. In such situations it would be extremely important that any dengue drug does not interact with other medications. Furthermore the aim to keep the cost of goods as low as possible would suggest that a potent drug with a long half-life would be desirable.

The decision to aim for an oral drug has an important influence on the choice of drug targets, as such drugs must be potent inhibitors of the chosen target protein, but more importantly possess the physicochemical properties to ensure good oral pharmacokinetics (Lipinski & Hopkins 2004). It is therefore essential to choose targets that are likely to be inhibited by drug-like molecules, since the success of a lead optimization often depends on the ability of chemists to produce compounds with good pharmacokinetics. With these considerations a target portfolio has been developed for the viral enzyme activities that are essential for its replication in infected cells.

TABLE 1 Dengue drug: target product profile (TPP)

Minimal product profile

Added value

Route of Administration Oral

Frequency of Dosing Clinical Efficacy

Patient Population

Others

Once a day

1. Reduces symptoms

2. Reduces incidence of severe dengue disease

3. Active against all 4 serotypes

1. Patients with severe Dengue symptoms.

2. High risk groups

3. Must be indicated for children ages 5 and up

Stable to heat/humidity; long shelf life; low/reasonable costs of goods; ease of formulation/low cost exipients

Also effective in other flaviviral diseases

1. Children younger than 5 years

2. Prophylactic use

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