Renal clearable catalytic gold nanoclusters for in vivo disease monitoring

Ultra-small gold nanoclusters (AuNCs) have emerged as agile probes for in vivo imaging, as they exhibit exceptional tumour accumulation and efficient renal clearance properties. However, their intrinsic catalytic activity, which can enable increased detection sensitivity, has yet to be explored for in vivo sensing. By exploiting the peroxidase-mimicking activity of AuNCs and the precise nanometer size filtration of the kidney, we designed multifunctional protease nanosensors that respond to disease microenvironments to produce a direct colorimetric urinary readout of disease state in less than 1 h. We monitored the catalytic activity of AuNCs in collected urine of a mouse model of colorectal cancer where tumour-bearing mice showed a 13-fold increase in colorimetric signal compared to healthy mice. Nanosensors were eliminated completely through hepatic and renal excretion within 4 weeks after injection with no evidence of toxicity. We envision that this modular approach will enable rapid detection of a diverse range of diseases by exploiting their specific enzymatic signatures

Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism

Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus-cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV

Reactivity and Mechanism in the Hydrolysis of β-Sultams

-Sultams show extraordinary rate enhancements of 109- and 107-fold, respectively, compared with the acid- and base-catalyzed hydrolysis of corresponding acyclic sulfonamides. They are about 103-fold more reactive than analogous -lactams. The alkaline hydrolysis of some -sultams shows a rate term that is second-order in hydroxide ion concentration, which is indicative of a stepwise mechanism involving a trigonal bipyramidal intermediate (TBPI). The Brnsted lg value for the alkaline hydrolysis of N-aryl--sultams is -0.58 and the kinetic solvent isotope effect / is 0.60, compatible with rate-limiting formation of the TBPI. Conversely, / for N-alkyl--sultams is 1.55, indicative of rate-limiting breakdown of the TBPI. The acid-catalyzed hydrolysis of -sultams is strongly retarded by electron-withdrawing groups to the sulfonyl group, and it is suggested that the mechanism may involve unimolecular ring opening to generate a sulfonylium ion. The Brnsted lg value for the acid-catalyzed hydrolysis of N-benzyl--sultams is 0.32. The general-acid-catalyzed hydrolysis of N-benzyl--sultam by carboxylic acids shows a Brnsted value of 0.67 and is attributed to a specific acid-nucleophilic mechanism with the formation of a mixed-anhydride intermediate