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Novel strategies for the prevention and control of persistent infections

Periodic Report Summary - NOPERSIST (Novel strategies for the prevention and control of persistent infections)

Project background and objectives:

Persistent infections such as Human Immunodeficiency Virus (HIV), tuberculosis? (TB) in humans and para-tuberculosis (ParaTB)-, mycoplasma-and Haemophilus-infections in farm animals are global health problems of immense social and economic importance. HIV-1 affects about 40 million people and M. tuberculosis infection is even higher world-wide.

Similarly, in addition to bovine tuberculosis, porcine respiratory infections caused by Mycoplasma and Haemophilus species are emerging pathogens already causing massive economic losses to the European pig industry which have been estimated to be in excess of 1 billion Euro per year. Diagnostis of all the these infections mentioned above is extremely difficult and time-consuming and no efficient, cost effective tests are available for an early diagnosis of these infections.

The main objectives of this project are:
1. To develop new drug candidates for drug resistant persistent infections (HIV and TB)
2. To identify and isolate novel antigens for the improved diagnosis of TB, ParaTB and infections in pigs
3. To identify antigens suitable for vaccine development for these persistent infections
4. To develop marketable, improved diagnostic products within a period of 2-3 years following the completion of this project

Project results:

1. Since the beginning of the project, a large number of natural products and synthetic compounds were provided by HZI to LIO. A selected number of compounds were formulated by LIO in cocktails and provided to ITM who as planned tested these against a number of drug resistant and drug sensitive strains collected from all over the world. Extensive data was provided by ITM to LIO. 2. In addition, LIO perfomed screening of 24000 substances using M. tuberculosis cultures and identified a series of inhibitors. 3. Libraries of M. hyorhinis and H. parasuis and their genome sequencing was completed as planned, 4. preparations of expression libraries of the pathogens has been partially completed, 5. cytotoxicity testing of substances identified during HT screens was completed. 6. The substances of the HZI library were assayed against AlaDH and 53 inhibitors were identified out of which one is highly promising in inhibiting target activity in nanomolar range. 7. RTDP KI performed tremendous amount of work on expression screens for HIV target CDK9 and finally noted the difficulty in expressing this target as soluble protein. Several strains and conditions were tried and significant expression was obtained but unfortunately as inclusion bodies. 8. KI did successfully complete work on M. tuberculosis target ALADH where final work on cocrystalisation is in progress. 9. LIONEX produced second lots of crude preparations of M. ulcerans toxin and provided these to RTDP HZI who is now busy purifying the toxin. 10. The work on synthesis of chemical analogues of Corallopyronin went as planned and LIONEX received the compounds from HZI which were tested in RNAP assays but proved not very effective. 11. UNIFI performed the collection of samples as planned and provided these to LIONEX. This work has resulted in the final preparation of a patent. 12. RTDP VLA tested a purified antigen library provided by LIONEX and were successful in identifying at least one highly promising antigen for use in TB vaccine development. This development has led another patent application which is being prepared for filing.

Potential Impact:

The progress of the project uptill now has been highly satisfactory and shall have significant impact on our objective of obtaining effective drug formulations and diagnostic reagents for the persistent infections. Patent filing is already in progress. IVD is already developing a diagnostic product based on the results obtained in the project. We are confident that further new products shall be developed as planned. Any success in the objectives mentioned shall have considerable social impact since prevention and control of these persistent infections is the primary global objective.
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