Protein stabilization is a “Holy Grail” of biocatalysis, and stability design is an area of intense research interest. While it is increasingly feasible to effectively increase enzyme thermostability, optimization without compromising activity or selectivity remains a significant challenge. Here, we use full-atom protein sequence design with sidechain conditioning (FAMPNN) to engineer thermostable variants of the borneol dehydrogenase from Salvia rosmarinus (SrBDH1), an enzyme from a family where unselective enzymes dominate, and selectivity is determined by dynamical considerations. By combining FAMPNN design with residue conservation analysis and avoiding active site residues, we were able to computationally design SrBDH1 variants with up to 10 °C enhanced thermostability and strongly increased half-life time at elevated temperature, while retaining selectivity towards (+)-borneol. This design framework, integrating de novo and physics-based protein design tools, demonstrates that stability can be enhanced without disrupting functionally relevant dynamics, providing a route to engineer robust and selective biocatalysts.

Double-stranded RNA (dsRNA) has become an essential tool to understand biological processes with promising therapeutic implications. However, its usage is often limited due to poor cellular uptake and...

The function and stability of proteins depend on their three-dimensional structure, which includes conformational dynamics and potential self-assembly. Protein structural organization is particularly ...

Phosphodiester groups occur ubiquitously in nature, e.g. in nucleic acids or in cyclic (di-)nucleotides important for signal transduction. Proteins often use polar or positively charged amino acids t...

N-heterocyclic carbenes (NHCs) have emerged as a versatile and powerful class of ligands in surface chemistry, offering remarkable stability and tunability when bound to surfaces, including metals, me...

Chronic lung infections caused by Pseudomonas aeruginosa and Burkholderia cenocepacia pose a severe threat to immunocompromised patients, particularly those with cystic fibrosis. These pathogens often...

Peptides are highly selective organocatalysts, with intrinsic modularity allowing precise control over structure and function. Advances in peptide synthesis, biotechnology, and cheminformatics will en...

Electrostatics play a dominant role in guiding many biological processes. This is especially the case in the context of chromatin, where charge interactions modulate diverse activities such as DNA rep...

The structure and function of the MCR activation complex from Methanococcus maripaludis were revealed, demonstrating its ATP-dependent ability to activate MCR and form methane while uncovering a uniqu...

Researchers developed DELTA, a method for brain-wide measurement of synaptic protein turnover with single-synapse resolution, providing a powerful tool to localize and study mechanisms underlying syna...

Axonal transcriptomes have been characterized, but their regulation and role in neuronal circuits remain unclear. Here authors uncover activity-dependent RNA localization in axons important for memory...

Bispecific antibodies incorporating a cross-reactive NTD-specific antibody are resilient to SARS-CoV-2 variants of concern.

Halda Therapeutics has started a clinical trial of its first-in-modality RIPTAC drug HLD-0915 in prostate cancer, to see if bifunctional drugs can provide tissue-specific activity.

Biomolecular mimics are intended to outperform their natural counterparts. However, B-DNA surface mimicry to target DNA-binding proteins has long remained underdeveloped. We have introduced helical a...

Cobalt-mimochrome VI*a (CoMC6*a), a cobalt synthetic mini-enzyme with a cobalt porphyrin active site, is developed as a biomolecular catalyst for electrocatalytic CO2 reduction in water. The catalytic...

First-in-human clinical trial to evaluate safety and tolerability of a new class of small molecule medicines for the treatment of cancer, RIPTAC™ therapeutics NEW HAVEN, CT, February 24, 2025 – Halda ...

A reconstituted cccDNA platform facilitated the discovery of an early chromatinization event that promotes transcription of the hepatitis B virus (HBV) regulatory X gene. The use of a small-molecule c...

So you’ve discovered a reaction. But how do you turn this new discovery into a fully-fledged program that maximises the potential of your novel transformation? Herein, we provide a student's checklist...

In biological processes, peptide bonds are formed via reactive phosphate-containing intermediates, facilitated by compartmentalized environments. Here, the authors use aminoacyl phosphate esters that ...

With increasing focus on sustainability, there has been a growth in the development of edible films to improve food quality, particularly with polysac…

This paper reports highly active analogues of clovibactin in which the rare, noncanonical amino acid d-hydroxyasparagine is replaced with the commercially available amino acid d-threonine. Sequential ...

A concise and convergent synthesis of the isosteroidal alkaloids veratramine and 20-iso-veratramine has been accomplished. A Horner–Wadsworth–Emmons olefination joins two chiral building blocks of app...

Andy Extance charts how research into revolutionary targeted protein degradation therapies is moving from serendipity to strategic discovery

A platform for the continuous selection of protein aggregation inhibitors from genetically encoded cyclic peptide libraries in Escherichia coli was developed. This platform was used to discover cyclic...

The term “undruggable” refers to proteins or other biological targets that have been historically challenging to target with conventional drugs or therapeutic strategies because of their structural, functional, or dynamic properties. Drugging such undruggable targets is essential to develop new therapies for diseases where current treatment options are limited or nonexistent. Thus, investigating methods to achieve such drugging is an important challenge in medicinal chemistry. Among the numerous methodologies for drug discovery, covalent modification of therapeutic targets has emerged as a transformative strategy. The covalent attachment of diverse functional molecules to targets provides a powerful platform for creating highly potent drugs and chemical tools as well the ability to provide valuable information on the structures and dynamics of undruggable targets. In this review, we summarize recent examples of chemical methods for the covalent modification of proteins and other biomolecules for the development of new therapeutics and to overcome drug discovery challenges and highlight how such methods contribute toward the drugging of undruggable targets. In particular, we focus on the use of covalent chemistry methods for the development of covalent drugs, target identification, drug screening, artificial modulation of post-translational modifications, cancer specific chemotherapies, and nucleic acid-based therapeutics.

Sterol transport proteins mediate intracellular sterol transport, organelle contact sites, and lipid metabolism. Despite their importance, the similarities in their sterol-binding domains have made th...