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EC centralized facility and concerted action on design, synthesis, evaluation and development of new antiviral compounds against AIDS

Objective

This Concerted Action/Centralized Facility should be viewed as the continuation of the EC AIDS Basic Research Programme aimed at the discovery of new antiviral compounds for the treatment of AIDS. This concerted action requires the cooperative help of more than 100 collaborating centers worldwide (about half of which belonging to EC countries). The primary objective is focused on the detection of active ?lead? compounds for the treatment of AIDS. This is based on a first-line evaluation of anti-HIV activity in an automatized cell assay system, complemented by second-line evaluation of the candidate lead compounds against various virus strains using various cell types and assay systems. As molecular targets within the HIV replicative cycle that should be amenable to chemotherapeutic attack, we have envisaged the following: virus adsorption, virus-cell fusion, viral uncoating, reverse transcription (viral RNA provire/DNA), proviral DNA integration, transcription and translation, post-translational modification, budding and maturation. The truly active compounds that emerge from the first- and second-line evaluation will have to be examined for their mechanism of action, and, in particular, their molecular targets of action will have to be elucidated. Through the comparative evaluation of a great number of compounds within a given class we should be able to delineate the structural requirements for anti-HIV activity. Based on the insight in the structure-activity relationship (SAR) of the ?lead? compounds, combined with the insight in the molecular coordinates of their target site, it should be possible through the aid of molecular modelling, to further design and refine the optimal anti-HIV drug candidate(s). Following chemical synthesis, these anti-HIV drug candidates should then be examined for their in vivo efficacy and pass the necessary pharmacokinetic and toxicological tests before being taken up to phase I/II clinical trials in patients with AIDS.
A high input facility for the evaluation of potential anti human immunodeficiency virus drugs has been developed that allows identification of lead compounds for the treatment of HIV infections. These compounds are then examined for their mechanism of action and molecular target with which they interact. The compounds can then be further refined through molecular modelling followed by chemical synthesis to optimize their interaction with their molecular target size, and, hence to achieve optimal activity and selectivity against HIV. This 'lead optimization' must then permit the identification of the optimal anti acquired immune deficiency syndrome (AIDS) drug candidate that after the necessary pharmacokinetic and toxicological studies should be further pursued.

Through this system, several drug candidates that should be pursued for the therapy and/or prophylaxis of HIV infections have been identified:
polyanionic substances that interfere with the virus adsorption step;
plant lectins, succinylated and aconitylated albumins, and betulinic acid derivatives, that interfere with the virus cell fusion process;
bicyclam derivatives that are assumed to interact with a viral uncoating;
reverse transcriptase inhibitors, that interact as chain terminators with the substrate binding site of the enzyme;
reverse transcriptase inhibitors, that interact specifically with a nonsubstrate binding site of the HIV-1 associated reverse transcriptase. The latter inhibitors, which have also been referred to as nonnuceloside reverse transcriptase inhibitors (NNRTI), are highly selective in their action against HIV-1 but permit the rapid emergence of virus drug resistance. Future strategies will be principally aimed at preventing or circumventing this resistance development.
Using a number of assay methods, with various HIV strains and cell systems, a high input facility for the evaluation of potential anti-HIV drugs has been developed that would allow to identify, from the vast number of compounds synthesized by the collaborating centers, new ‘lead’ compounds for the treatment of HIV infections (ie AIDS). These ‘lead’ compounds are then examined for their mechanism of action and molecular target (within the HIV replicative cycle) with which they interact. Based on the structure-function relationship of the active compounds, as well as the molecular coordinates of the target site, the ‘lead’ compounds can be further refined, through molecular modelling followed by chemical synthesis, so as to optimize their interaction with their molecular target site, and, hence, to achieve optimal activity and selectivity against HIV. This ‘lead optimization’ must then permit the identification of the optimal anti-AIDS drug candidate(s) that, after the necessary pharmacokinetic and toxicological studies, should be further pursued in the clinic for their potential in the therapy and/or prophylaxis of AIDS.

Breakthroughs

We have identified various ‘lead’ compounds, and among these ‘lead’ compounds, several drug candidates that should be further pursued for the therapy and/or prophylaxis of HIV infections:
1 polyanionic substances (ie polysulfates, polysulfonates, polycarboxylates, polyoxometalates), that interfere with the virus adsorption step
2 plant lectins, succinylated and aconitylated albumins, and betulinic acid derivatives, that interfere with the virus-cell fusion process
3 bicyclam derivatives that are assumed to interact with a viral uncoating (dissociation of viral RNA from the viral capsid proteins)
4 reverse transcriptase inhibitors, ie acyclic nucleoside phosphonates, that interacts as ‘chain terminators’ with the substrate binding site of the enzyme
5 reverse transcriptase inhibitors, i.e. TIBO, HEPT, TSAO and alpha-APA derivatives, that interact specifically with a non-substrate binding site of the HIV-1-associated reverse transcriptase.

The latter inhibitors, which have also been referred to as NNRTIs (‘non-nucleoside reverse transcriptase inhibitors’), are highly selective in their action against HIV-1 but permit the rapid emergence of virus-drug resistance. Therefore, future strategies will be principally aimed at preventing or circumventing this resistance development.

Funding Scheme

CON - Coordination of research actions

Coordinator

Katholieke Universiteit Leuven
Address
Minderbroedersstraat 10
3000 Leuven
Belgium