Publications

A series of diketo derivatives was found to inhibit human immunodeficiency virus type 1 (HIV-1) integrase activity. Only L-708,906 inhibited the replication of HIV-1(III(B)) (50% effective concentration, 12 micro M), HIV-1 clinical strains, HIV-1 strains resistant to reverse transcriptase or fusion inhibitors, HIV-2 (ROD strain) and simian immunodeficiency virus (MAC(251)). The combinations of L-708,906 with zidovudine, nevirapine, or nelfinavir proved to be subsynergistic. In cell culture, addition of L-708,906 could be postponed for 7 h after infection, a moment coinciding with HIV integration. Inhibition of integration in cell culture was confirmed by quantitative Alu-PCR.

Several drug-resistant herpes simplex virus type 1 (HSV-1) strains were obtained under the selective pressure of various antiherpetic drugs used alone or in combination. Their susceptibility to a wide range of antiviral compounds was determined. Strains selected under the pressure of brivudin (BVDU) or 1-β-D-arabinofuranosyl-( E)-5-(2-bromovinyl)uracil (BVaraU) alone were composed of two virus populations: (1) virus resistant to BVDU and BVaraU but not to acyclovir (ACV) or ganciclovir (GCV), which is suggestive of an alteration in the thymidylate kinase activity associated with the viral thymidine kinase (TK) (responsible for the phosphorylation of BVDU-monophosphate to BVDU-diphosphate); and (2) virus resistant to BVDU, BVaraU, ACV and GCV, which is indicative of an alteration in the viral TK activity that converts BVDU, BVaraU and other nucleoside analogues such as ACV and GCV to their monophosphate derivatives. Strains resistant to TK-dependent drugs (i.e. ACV, GCV, BVDU and BVaraU) as well as double-mutant strains with decreased sensitivity to both TK-dependent compounds and the pyrophosphate analogues foscarnet (PFA) and phosphonoacetic acid (PAA) (suggestive of mutations at the level of the DNA polymerase) were recovered under the selective pressure of ACV alone or in combination with BVDU or BVaraU. Combinations of BVDU or BVaraU with PFA or PAA led to strains resistant only to BVDU and BVaraU or double-mutant strains resistant to BVDU, BVaraU and the pyrophosphate analogues, but not to strains resistant to other TK-dependent drugs. Interestingly, strains resistant to ACV, BVDU, GCV and/or the pyrophosphate analogues PFA and PAA remained sensitive to the (S)-3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of cytosine (HPMPC) and adenine (HPMPA).

Thales Electron Devices has been pursuing since 2003 frequency standards activities. In the framework of these activities, Thales established a consortium for the development of a space Cs atomic clock for Galileo. This consortium is composed by two of the best scientific laboratories in the European Time-Frequency community : the Observatoire de Neuchâtel (ON) and the SYRTE Observatoire de Paris, and by two space industrials : Oerlikon Space AG (OSAG) and Thales Electron Devices. The name of the project is OSCC for Optically pumped Space Cs Clock. The first phase (phase A) of this development started in June 2006 under an ESA contract. The purpose of this phase A is a feasibility study of Cs clock technology for Galileo with the manufacturing and the test of a new compact optically pumped Cs clock breadboard. This technology is well known in laboratories but it has never been industrialized, even for ground applications. This study starts with a strong background at SYRTE and ON, but also with new industrial developments realized at Thales during the last years. Frequency stability in order of 1 to 3×10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-12</sup> .τ <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">-½</sup> has been already demonstrated in lab with different configurations. This document will first synthesize the last results obtained by each Partner, followed by the results of the existing hardware analysis performed in the first step of the project. This analysis allowed Partners to share their know-how and to identify the limits of each existing breadboards with respect to the objectives of the project.