Hiv-1 Specific Reverse Transcriptase Inhibitors: why are Tsao-Nucleosides so Unique?

1. INTRODUCTION

AIDS will still be one of the most important challenges for the Scientific Community in the approaching new century. Since the identification, in 1983-84,^1,2 of human immunodeficiency virus (HIV) as the etiological agent of AIDS, significant progress has been made in the treatment of HIV-infected patients. This has been in part due to the discovery and clinical use of an increasing number of anti-HIV drugs. However, while highly active antiretroviral therapy (HAART)³ approaches have reduced the morbidity and mortality, the intertwined problems of drug induced viral resistance, poor compliance with complex regimens and therapy failure continue. Therefore, there remains a pressing need for the development of new antiviral agents that can be used not only as first line therapeutic candidates, but also in the antiretroviral-experienced patient population.     

Transmission of HIV in sexual networks in sub-Saharan Africa and Europe

We are reviewing the literature regarding sexual networks and HIV transmission in sub-Saharan Africa and Europe. On Likoma Island in Malawi, a sexual network was reconstructed using a sociometric survey in which individuals named their sexual partners. The sexual network identified one giant component including half of all sexually active individuals. More than 25% of respondents were linked through independent chains of sexual relations. HIV was more common in the sparser regions of the network due to over-representation of groups with higher HIV prevalence. A study from KwaZulu-Natal in South-Africa collected egocentric data about sexual partners and found that new infections in women in a particular area was associated with the number of life-time partners in men. Data about sexual networks and HIV transmission are not reported in Europe. It is, however, found that the annual number of sexual partners follows a scale-free network. Phylogenetic studies that determine genetic relatedness between HIV isolates obtained from infected individuals, found that patients in the early stages of infections explain a high number of new infections. In conclusion, the limited information that is available suggest that sexual networks play a role in spread of HIV. Obtaining more information about sexual networks can be of benefit for modeling studies on HIV transmission and prevention.     

A theoretical NMR study of the structure of benzynes and some of their carbocyclic and heterocyclic analogs

This work reports the theoretical study of the aromaticity of a series of carbocycles (benzene, cyclohexane, bent and planar cyclooctatetraene) and heterocycles (pyridine, furan, thiophene, pyrrole) and their didehydro forms (arynes and hetarynes). As aromaticity probe Schleyer's NICS were used and represented in two 3D isosurfaces of the electron density. The spatial 3D representation of the NICS is shown to be a powerful tool to visualize the aromaticity (or its absence) of different molecules.     

Directed ortho-lithiation of unprotected diphenylphosphinic acids

Directed ortho lithiation of diphenylphosphinic acid and subsequent electrophilic trapping provides mono ortho-functionalized derivatives including enantiopure γ-aminophosphinic acids in moderate yields. Copper catalyzed coupling of the ortho anion leads to biphenyl-2,2′-diylbis(phenylphosphinic acid), a phosphorus analogue of biphenyl-2,2′-dicarboxylic acid. Preliminary studies of the metal-binding abilities of this O,O-chelating ligand towards a series of metal cations are included.     

Multiple Keys for a Single Lock: The Unusual Structural Plasticity of the Nucleotidyltransferase (4′)/Kanamycin Complex

The most common mode of bacterial resistance to aminoglycoside antibiotics is the enzyme‐catalysed chemical modification of the drug. Over the last two decades, significant efforts in medicinal chemistry have been focused on the design of non‐ inactivable antibiotics. Unfortunately, this strategy has met with limited success on account of the remarkably wide substrate specificity of aminoglycoside‐modifying enzymes. To understand the mechanisms behind substrate promiscuity, we have performed a comprehensive experimental and theoretical analysis of the molecular‐recognition processes that lead to antibiotic inactivation by Staphylococcus aureus nucleotidyltransferase 4′(ANT(4′)), a clinically relevant protein. According to our results, the ability of this enzyme to inactivate structurally diverse polycationic molecules relies on three specific features of the catalytic region. First, the dominant role of electrostatics in aminoglycoside recognition, in combination with the significant extension of the enzyme anionic regions, confers to the protein/antibiotic complex a highly dynamic character. The motion deduced for the bound antibiotic seem to be essential for the enzyme action and probably provide a mechanism to explore alternative drug inactivation modes. Second, the nucleotide recognition is exclusively mediated by the inorganic fragment. In fact, even inorganic triphosphate can be employed as a substrate. Third, ANT(4′) seems to be equipped with a duplicated basic catalyst that is able to promote drug inactivation through different reactive geometries. This particular combination of features explains the enzyme versatility and renders the design of non‐inactivable derivatives a challenging task.     

A general and systematic framework for the kinematic analysis of complex gear systems

It is presented an integral approach for the velocity analysis of complex gear systems. Due to the intrinsic nature of the method, it can be systematically applied for gear trains with arbitrary architecture, including bevel gears with non-parallel motion axes. As a result, not only velocity ratios can be computed, but also angular velocities of any body composing the gear system. Several application examples are presented to prove the feasibility and the validity of the proposed method.     

DISSOLUTION OF IRON TO COPPER IN Fe60Cu40 ALLOY BY MECHANICAL ALLOYING AND SUBSEQUENT DECOMPOSITION

A metastable alloy with composition Fe₆₀Cu₄₀ can be prepared in single phase of a fcc structure by mechanical alloying, although Fe-Cu system is virtually immiscible in its equilibrium state at ambient temperature. The M?ssbauer spectra of this supersaturated solid solution could be fitted by two subspectra whose hyperfine magnetic fields are 200 kOe and 250kOe. In this metastable alloy, the iron atoms at the interface are easy to form clusters characterized as α-Fe at a temperature below 250℃, whereas the iron atoms in the body will cluster together at a higher temperature above 350℃ and behave as γ-Fe, and then transform to ferromagnetic bcc iron occurs.     

High-order squeezing of pure superposition states

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Contribution a L'etude de melanges susceptibles de former des microemulsions selon leurs compositions,par la definition de leurs comportements dielectriques a 9,455 GHz

The dielectric studies of four components mixtures are rarely made on a great deal of concentrations. The authors propose a dielectric behavior study of mixtures made with toluene-water-butanol-SDS, from specific mappings of permittivities which are plotted on pseudo ternary diagrams at 9.455 GHz. They draw different conclusions to know how at 9.455 GHz the variations of real and imaginary parts of permittivity involve the concentration of each component and the structure of the mixture.These conclusions will be perfected by studies made at other frequencies and by spectral analysis of each mixture.     

Study of Intramolecular Cyclization of N-styryl-oxo-cinnamides (Ⅱ)

lnthepreviouspaper',wereportedtheintramolecularcyclizationsofamide4anditscis-eneisomerinanattempttosynthesizehomoclausenamideandzetaclausenamide2.Inordertostudytherelationshipbetweenthestereochemistryandtheilltramolecularcyclizationofthisseriesofcompounds,theamides5(cis-oxirane,trans-ene)and8(cis-oxirane,cis-ene)wereprepared,andtheirintramolecularcyclizationswerereportedinthispaper.Theamide5withm.p.152.O-l54.O"CwasobtainedfromDarzen'scondensationofcompound3withPhCHOinMeOHatl5-2OoCwithMeO…