O.B. thanks the European Commission (Marie Curie CIG) and Ministerio de Ciencia e Innovacion, Spain (Juan de la Cierva Fellowship). G.J.L.B. thanks his generous sources of funding: Royal Society, FCT Portugal (FCT Investigator), European Commission (Marie Curie CIG), and the EPSRC. G.J.L.B. is a Royal Society University Research Fellow. The authors thank Paula Boutureira Regla and Francisco Pinteus da Cruz Lopes Bernardes for inspiration.

Advances in Chemical Protein Modification

Chemical modification of proteins is an important tool for probing natural systems, creating therapeutic conjugates and generating novel protein constructs. Site-selective reactions require exquisite control over both chemo- and regioselectivity, under ambient, aqueous conditions. There are now various methods for achieving selective modification of both natural and unnatural amino acids--each with merits and limitations--providing a 'toolkit' that until 20 years ago was largely limited to reactions at nucleophilic cysteine and lysine residues. If applied in a biologically benign manner, this chemistry could form the basis of true Synthetic Biology.

/pdf/selective-chemical-protein-modification-4z476j40wm.pdf

Selective chemical protein modification

Colloidal inorganic nanocrystals stand out as an important class of advanced nanomaterials owing to the flexibility with which their physical-chemical properties can be controlled through size, shape, and compositional engineering in the synthesis stage and the versatility with which they can be implemented into technological applications in fields as diverse as optoelectronics, energy conversion/production, catalysis, and biomedicine. The use of microwave irradiation as a non-classical energy source has become increasingly popular in the preparation of nanocrystals (which generally involves complex and time-consuming processing of molecular precursors in the presence of solvents, ligands and/or surfactants at elevated temperatures). Similar to its now widespread use in organic chemistry, the efficiency of "microwave flash heating" in dramatically reducing overall processing times is one of the main advantages associated with this technique. This Review illustrates microwave-assisted methods that have been developed to synthesize colloidal inorganic nanocrystals and critically evaluates the specific roles that microwave irradiation may play in the formation of these nanomaterials.

Microwave-assisted synthesis of colloidal inorganic nanocrystals.

Supramolecular chemistry in water is a constantly growing research area because noncovalent interactions in aqueous media are important for obtaining a better understanding and control of the major processes in nature. This Review offers an overview of recent advances in the area of water-soluble synthetic receptors as well as self-assembly and molecular recognition in water, through consideration of the functionalities that are used to increase the water solubility, as well as the supramolecular interactions and approaches used for effective recognition of a guest and self-assembly in water. The special features and applications of supramolecular entities in aqueous media are also described.

Supramolecular Chemistry in Water

Brass AL, Dykxhoorn DM, Benita Y, et al. Science . 2008;319(5865):921–926 PURPOSE OF THE STUDY. The HIV genome encodes only 15 proteins and, therefore, must use multiple host-cell collaborators for successful replication and transmission. Required host-derived proteins include CD4 as the primary virus receptor and chemokine receptors as coreceptors. This study identified multiple other host proteins required for HIV activity. METHODS. Human cells known to be susceptible to HIV were exposed in vitro to HIV. Using small interfering RNAs able to inhibit each known gene in the human genome 1 at a time, the investigators tested whether HIV could establish an infection and copy itself. HIV dependence on >21 000 human genes was examined. RESULTS. More than 250 human genes were identified to be required for efficient HIV replication. Termed “HIV-dependency factors,” the products of these genes are known to participate in a broad array of cellular functions and implicate unsuspected pathways in the virus life cycle. CONCLUSIONS. The extraordinary dependence of HIV on human host proteins for efficient transmission and replication provides many new potential targets for antiretroviral therapy. REVIEWER COMMENTS. An example of targeting host proteins is the use of chemokine receptor 5 (CCR5) inhibitors. Many people with CCR5 deficiency are very resistant to HIV infection yet have limited if any clinical consequences. Maraviroc CCR5 inhibitor is approved for treatment for HIV infection. This study identified many more such potential targets.

Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen

http://aether.cmi.ua.ac.be/artikels/Artikels%20Gitte/Artikels/Reviews/microwave%20enhanced%20synthesis%20Caddick%202009.pdf

Microwave enhanced synthesis

Synthetic receptors for carboxylic acids and carboxylates

The development of methods for carbon-carbon bond formation under benign conditions is an ongoing challenge for the synthetic chemist. In recent years there has been considerable interest in using selective C-H activation as a direct route for generating reactive intermediates. In this article, we describe the use of aldehyde auto-oxidation as a simple, clean and effective method for C-H activation, resulting in the generation of an acyl radical. This acyl radical can be used for carbon-carbon bond formation and herein we describe the application of this method for the hydroacylation of alpha,beta-unsaturated esters without the requirement of additional catalysts or reagents. This methodology generates unsymmetrical ketones, which have been shown to have broad use in organic synthesis.

Hydroacylation of α,β-unsaturated esters via aerobic C–H activation

Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened a library of isoxazolidine and isoxazole sulfonamides and found four compounds that inhibited HIV-1 infection in human CD4+ lymphocytic T cells with no toxicity at IC90 concentrations. Structure-activity relationship showed that benzyl sulfonamides and a halo-substituted aromatic ring on the heterocycle scaffold were critical for antiretroviral activity. The size and position of the incorporated halogen had a marked effect on the antiretroviral activity. The sulfonamide derivatives had no significant effect on HIV-1 entry, reverse transcription and integration but impaired a step necessary for activation of viral gene expression. This step was Tat-independent, strongly suggesting that the target is a cell factor. A virus partially resistant to the least potent compounds could be selected but could not be propagated in the long term, consistent with the possibility that HIV-1 may be less likely to develop resistance against drugs targeting some host factors. Here, we provide evidence that novel synthetic methods can be applied to develop small molecules with antiretroviral activity that target host factors important for HIV-1 replication.

/pdf/inhibition-of-hiv-1-replication-by-isoxazolidine-and-21n0i58shv.pdf

Inhibition of HIV-1 replication by isoxazolidine and isoxazole sulfonamides.

http://www.rsc.org/suppdata/CC/b9/b914563j/b914563j.pdf

Richard J. Fitzmaurice

Papers

Microwave enhanced synthesis

Synthetic receptors for carboxylic acids and carboxylates

Hydroacylation of α,β-unsaturated esters via aerobic C–H activation

Inhibition of HIV-1 replication by isoxazolidine and isoxazole sulfonamides.

Dioxygen mediated hydroacylation of vinyl sulfonates and sulfones on water.