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We developed a rational approach to design peptide-based covalent inhibitors and coupled the inhibitors with antibodies for cell-specific delivery. We used this platform to generate antibody–peptide inhibitor conjugates (APICs) that target a family of proteases, the cysteine cathepsins. Our drug design and targeted delivery approach ensure specific inhibition and achieve therapeutic efficacy in different cancer cells and osteoclasts.

Jiang et al. developed a computational method to design repeat proteins with multiple structured loops that are buttressed by extensive hydrogen bond networks. The designs were further functionalized into high-affinity peptide-binding proteins.

Huang et al. report the tertiary structure of a small monomeric fluorogenic RNA aptamer named Clivia, characterized by a large Stokes shift, revealing the fluorescence activation mechanism and enabling a multivalent design to enhance the fluorescence output at specific dye concentrations.

Cathepsins are relevant therapeutic targets in cancer and other diseases. Here, the authors developed a different approach to block the activity of cathepsins in specific cellular contexts by combining non-natural peptide inhibitors with antibodies, enhancing therapeutic efficacy while reducing side effects.

The ZDHHC family of palmitoyl transferases lipidates numerous protein targets, but the paucity of selective inhibitors has hindered their target profiling. A generalized chemical genetic system can now map the protein targets of individual ZDHHC family members.

Targeted protein degradation has emerged as a promising approach in drug discovery, harnessing a cell’s intrinsic machinery to eliminate disease-related proteins. Now, a study paves the way to translating this technology into potential anti-mycobacterial therapies, by exploiting the bacterial protein-degradation complex.

Zuo et al. developed a highly bright and stable green fluorescent RNA for robust imaging of the dynamics of messenger RNA in living cells, enabling visualization of nonuniform and distinct distributions of different RNAs throughout stress granules.

Engineered living materials harness the computational power of biology to control interesting material properties. Here the authors leverage complex transcriptional regulation of bacterial extracellular electron transfer to control hydrogel cross-linking with Boolean logic.

Reliably identifying ubiquitin ligase interactors and substrates has been a persistent challenge in cellular biology. A breakthrough comes in the form of a potent, selective and cell-active chemical probe, shedding light on the intricate functions of a key regulatory enzyme.

Owens et al. reported PFI-7, a selective and potent antagonist of GID4 of the CTLH E3 ligase complex, which enables identification of human GID4 targets. This study provides valuable insights into GID4 functions and a powerful tool for advancing new targeted protein degradation strategies.

Yin et al. discover that the phosphatase PTENα acts as an RNA-binding protein, mitigating viral-induced inflammation in the brain by constraining RIG-I activation, suggesting PTENα as a potential therapeutic target for viral infection.

A newly developed maternally selective nanobody antagonist against the angiotensin II type I receptor stabilizes the receptor in a hybrid conformation and simultaneously binds with specific small-molecule antagonists.

Biochemical pathways for aromatic amino acid synthesis are ancient and highly conserved. Directed evolution of the β-subunit of tryptophan synthase (TrpB)—a proficient biocatalyst that converts indole to l-tryptophan—enabled this enzyme to make l-tyrosines from phenols, a pathway not (yet) known in nature.

Natural ribozymes can cleave RNA and single-stranded DNA (ssDNA) by transesterification or a blend of hydrolytic and transesterification reactions. Now, ribozymes have been discovered that catalyze the hydrolytic cleavage of ssDNA. Similar ribozymes could potentially replace large, immunogenic, protein-based nucleases in gene therapies.

Ferroptosis, a cell death mechanism induced by lipid peroxidation, is pivotal in tumor suppression. A recent study shows that tumor repopulating cells evade ferroptosis and develop resistance to therapy via subverting a lipid metabolism enzyme.

Phosphorylation of ACSL4 by mitochondria-located metabolic kinase PCK2 is critical to regulating ferroptosis-associated phospholipid remodeling in tumor-repopulating cells that are resistant to chemotherapy and radiotherapy.

We present a discovery pipeline integrating chemical fragment screening and time-resolved, high-throughput small-angle X-ray scattering (TR-HT-SAXS). This approach identifies allosteric chemical leads targeting distinct allosteric states of the mitochondrial oxidoreductase apoptosis-inducing factor (AIF). By monitoring kinetic rates of allosteric transition with TR-HT-SAXS, we link fragment structure–activity relationships (SARs) to biomolecular conformation.