Dataset Information

'Chemistry at the speed of sound': automated 1536-well nanoscale synthesis of 16 scaffolds in parallel.

ABSTRACT: Screening of large and diverse libraries is the 'bread and butter' in the first phase of the discovery of novel drugs. However, maintenance and periodic renewal of high-quality large compound collections pose considerable logistic, environmental and monetary problems. Here, we exercise an alternative, the 'on-the-fly' synthesis of large and diverse libraries on a nanoscale in a highly automated fashion. For the first time, we show the feasibility of the synthesis of a large library based on 16 different chemistries in parallel on several 384-well plates using the acoustic dispensing ejection (ADE) technology platform. In contrast to combinatorial chemistry, we produced 16 scaffolds at the same time and in a sparse matrix fashion, and each compound was produced by a random combination of diverse large building blocks. The synthesis, analytics, resynthesis of selected compounds, and chemoinformatic analysis of the library are described. The advantages of the herein described automated nanoscale synthesis approach include great library diversity, absence of library storage logistics, superior economics, speed of synthesis by automation, increased safety, and hence sustainable chemistry.

SUBMITTER: Gao L

PROVIDER: S-EPMC9940305 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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'Chemistry at the speed of sound': automated 1536-well nanoscale synthesis of 16 scaffolds in parallel.

Gao Li L Shaabani Shabnam S Reyes Romero Atilio A Xu Ruixue R Ahmadianmoghaddam Maryam M Dömling Alexander A

Green chemistry : an international journal and green chemistry resource : GC 20230117 4

Screening of large and diverse libraries is the 'bread and butter' in the first phase of the discovery of novel drugs. However, maintenance and periodic renewal of high-quality large compound collections pose considerable logistic, environmental and monetary problems. Here, we exercise an alternative, the 'on-the-fly' synthesis of large and diverse libraries on a nanoscale in a highly automated fashion. For the first time, we show the feasibility of the synthesis of a large library based on 16 d ...[more]

PMID: 36824604

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Project description:The ability to process and act upon incoming sounds during locomotion is critical for survival and adaptive behavior. Despite the established role that the auditory cortex (AC) plays in behavior- and context-dependent sound processing, previous studies have found that auditory cortical activity is on average suppressed during locomotion as compared to immobility. While suppression of auditory cortical responses to self-generated sounds results from corollary discharge, which weakens responses to predictable sounds, the functional role of weaker responses to unpredictable external sounds during locomotion remains unclear. In particular, whether suppression of external sound-evoked responses during locomotion reflects reduced involvement of the AC in sound processing or whether it results from masking by an alternative neural computation in this state remains unresolved. Here, we tested the hypothesis that rather than simple inhibition, reduced sound-evoked responses during locomotion reflect a tradeoff with the emergence of explicit and reliable coding of locomotion velocity. To test this hypothesis, we first used neural inactivation in behaving mice and found that the AC plays a critical role in sound-guided behavior during locomotion. To investigate the nature of this processing, we used two-photon calcium imaging of local excitatory auditory cortical neural populations in awake mice. We found that locomotion had diverse influences on activity of different neurons, with a net suppression of baseline-subtracted sound-evoked responses and neural stimulus detection, consistent with previous studies. Importantly, we found that the net inhibitory effect of locomotion on baseline-subtracted sound-evoked responses was strongly shaped by elevated ongoing activity that compressed the response dynamic range, and that rather than reflecting enhanced "noise," this ongoing activity reliably encoded the animal's locomotion speed. Decoding analyses revealed that locomotion speed and sound are robustly co-encoded by auditory cortical ensemble activity. Finally, we found consistent patterns of joint coding of sound and locomotion speed in electrophysiologically recorded activity in freely moving rats. Together, our data suggest that rather than being suppressed by locomotion, auditory cortical ensembles explicitly encode it alongside sound information to support sound perception during locomotion.

Project description:BackgroundDue to their natural tendency to self-assemble, proteins and peptides are important components for organic nanotechnology. One particular class of peptides of recent interest is those that form amyloid fibrils, as this self-assembly results in extremely strong, stable quasi-one-dimensional structures which can be used to organise a wide range of cargo species including proteins and oligonucleotides. However, assembly of peptides already conjugated to proteins is limited to cargo species that do not interfere sterically with the assembly process or misfold under the harsh conditions often used for assembly. Therefore, a general method is needed to conjugate proteins and other molecules to amyloid fibrils after the fibrils have self-assembled.ResultsHere we have designed an amyloidogenic peptide based on the TTR105-115 fragment of transthyretin to form fibrils that display an alkyne functionality, important for bioorthogonal chemical reactions, on their surface. The fibrils were formed and reacted both with an azide-containing amino acid and with an azide-functionalised dye by the Huisgen cycloaddition, one of the class of "click" reactions. Mass spectrometry and total internal reflection fluorescence optical microscopy were used to show that peptides incorporated into the fibrils reacted with the azide while maintaining the structure of the fibril. These click-functionalised amyloid fibrils have a variety of potential uses in materials and as scaffolds for bionanotechnology.DiscussionAlthough previous studies have produced peptides that can both form amyloid fibrils and undergo "click"-type reactions, this is the first example of amyloid fibrils that can undergo such a reaction after they have been formed. Our approach has the advantage that self-assembly takes place before click functionalization rather than pre-functionalised building blocks self-assembling. Therefore, the molecules used to functionalise the fibril do not themselves have to be exposed to harsh, amyloid-forming conditions. This means that a wider range of proteins can be used as ligands in this process. For instance, the fibrils can be functionalised with a green fluorescent protein that retains its fluorescence after it is attached to the fibrils, whereas this protein loses its fluorescence if it is exposed to the conditions used for aggregation.

Dataset Information

'Chemistry at the speed of sound': automated 1536-well nanoscale synthesis of 16 scaffolds in parallel.

Publications

'Chemistry at the speed of sound': automated 1536-well nanoscale synthesis of 16 scaffolds in parallel.

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