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Roger Condom

Publications and source records attributed to Roger Condom.

7 recordsLinked to original sources
PubMed2006

AZT and AZT-monophosphate prodrugs incorporating HIV-protease substrate fragment: synthesis and evaluation as specific drug delivery systems.

With the view to deliver anti-HIV nucleoside and nucleoside-monophosphate (MP) analogues specifically into HIV-infected cells, we synthesized a series of ester and phosphoramidate peptide conjugates of zidovudine (AZT) and of AZT-MP, respectively, wherein the peptide sequences derive from a HIV-protease (PR) hydrolysable substrate. Their in vitro stability with respect to hydrolysis, anti-HIV activity and cytotoxicity, and ability to inhibit the HIV-PR activity were investigated. Concerning the ester AZT-peptide conjugates, their antiviral activity level in thymidine kinase-expressing (TK+) CEM-SS and MT-4 cells was in most cases closely correlated to their hydrolysis rate: the faster the hydrolysis, the closer the anti-HIV activity to that of AZT. None of them was a HIV-PR substrate, indicating that their antiviral activity was not related to their intracellular hydrolysis by this enzyme. None of them inhibited HIV in TK-deficient (TK-) CEM cells, demonstrating that they probably act as prodrugs of AZT. Most of the phosphoramidate peptide conjugates of AZT-MP were rapidly degraded in a physiological buffer into several metabolites including AZT. Their anti-HIV activity in TK+ CEM-SS and MT-4 cells was much lower than that of AZT, indicating that only low amounts of AZT or AZT-MP were released into cells during incubation. Antiviral activities measured on TK- CEM cells for some phosphoramidates suggest that low amounts of AZT-MP could be released intracellularly. However, this AZT-MP release was not initiated by a HIV-PR hydrolysis, as no evidence for peptide cleavage was obtained by HPLC analysis of one representative compound after incubation with HIV-PR.

Amides↗
PubMed2005

A cyclic PNA-based compound targeting domain IV of HCV IRES RNA inhibits in vitro IRES-dependent translation.

A cyclic molecule 1 constituted by a hepta-peptide nucleic acid sequence complementary to the apical loop of domain IV of hepatitis C virus (HCV) internal ribosome entry site (IRES) RNA has been prepared via a 'mixed' liquid-phase strategy, which relies on easily available protected PNA and poly(2-aminoethylglycinamide) building blocks. This compound 1 has been elaborated to mimic 'loop-loop' interactions. For comparison, its linear analog has also been investigated. Although preliminary biological assays have revealed the ability of 1 to inhibit in vitro the HCV IRES-dependent translation in a dose-dependent manner, the linear analog has shown a slightly higher activity.

Hepacivirus↗
PubMed2004

Closing loop base pairs in RNA loop-loop complexes: structural behavior, interaction energy and solvation analysis through molecular dynamics simulations.

Nanosecond molecular dynamics using the Ewald summation method have been performed to elucidate the structural and energetic role of the closing base pair in loop-loop RNA duplexes neutralized by Mg2+ counterions in aqueous phases. Mismatches GA, CU and Watson-Crick GC base pairs have been considered for closing the loop of an RNA in complementary interaction with HIV-1 TAR. The simulations reveal that the mismatch GA base, mediated by a water molecule, leads to a complex that presents the best compromise between flexibility and energetic contributions. The mismatch CU base pair, in spite of the presence of an inserted water molecule, is too short to achieve a tight interaction at the closing-loop junction and seems to force TAR to reorganize upon binding. An energetic analysis has allowed us to quantify the strength of the interactions of the closing and the loop-loop pairs throughout the simulations. Although the water-mediated GA closing base pair presents an interaction energy similar to that found on fully geometry-optimized structure, the water-mediated CU closing base pair energy interaction reaches less than half the optimal value.

Aptamers, Nucleotide↗
PubMed2003

Molecular dynamics simulation of hepatitis C virus IRES IIId domain: structural behavior, electrostatic and energetic analysis.

The dynamic behavior of the HCV IRES IIId domain is analyzed by means of a 2.6-ns molecular dynamics simulation, starting from an NMR structure. The simulation is carried out in explicit water with Na+ counterions, and particle-mesh Ewald summation is used for the electrostatic interactions. In this work, we analyze selected patterns of the helix that are crucial for IRES activity and that could be considered as targets for the intervention of inhibitors, such as the hexanucleotide terminal loop (more particularly its three consecutive guanines) and the loop-E motif. The simulation has allowed us to analyze the dynamics of the loop substructure and has revealed a behavior among the guanine bases that might explain the different role of the third guanine of the GGG triplet upon molecular recognition. The accessibility of the loop-E motif and the loop major and minor groove is also examined, as well as the effect of Na+ or Mg2+ counterion within the simulation. The electrostatic analysis reveals several ion pockets, not discussed in the experimental structure. The positions of these ions are useful for locating specific electrostatic recognition sites for potential inhibitor binding.

Amino Acid Motifs↗
PubMed2003

Cyclic PNA-based compound directed against HIV-1 TAR RNA: modelling, liquid-phase synthesis and TAR binding.

A cyclic molecule including a hexameric PNA sequence has been designed and synthesized in order to target the TAR RNA loop of HIV-1 through the formation of a "kissing complex". For comparison, its linear analogue has also been investigated. The synthesis of the cyclic and linear PNA has been accomplished following a liquid-phase strategy using mixed PNA and fully N-protected (aminoethylglycinamide) fragments. The interactions of this cyclic PNA and its linear analogue with TAR RNA have been studied and the results indicate clearly that no interaction occurs between the cyclic antisense PNA and TAR RNA, whereas a tenuous interaction has been detected with its linear PNA analogue.

Cyclization↗
PubMed2002

Modelling, synthesis and biological evaluation of an ethidium-arginine conjugate linked to a ribonuclease mimic directed against TAR RNA of HIV-1.

Using molecular modelling studies, an active anti-HIV ethidium-arginine conjugate targeted against the viral TAR RNA sequence has been linked to an artificial ribonuclease, with the aim to obtain an irreversible inhibitor. The ribonuclease moiety consists of an N-[N-(3-aminopropyl)-3-aminopropyl] glycine and has been constructed via two successive N-alkylations following the Fukuyama procedure.

Alkylation↗