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  • The inaugural CRISPR-based drug Casgevy has been approved by several medical agencies, with other CRISPR-based therapies currently in clinical trials. Although there are technological hurdles to overcome, chemical biology has a vital role in developing recent breakthroughs in base editing, prime editing and epigenetic editing into future treatments.

    • Yitong Ma
    • Lei S. Qi
  • The kinesin-1 motor protein accesses open active and closed autoinhibited states. These states are regulated by a flexible elbow within a complex coiled-coil architecture. Now, a conformational switch has been developed by engineering the elbow to create a closed state that can be controllably opened with a de novo designed peptide to increase kinesin transport inside cells.

    • Jessica A. Cross
    • William M. Dawson
    • Derek N. Woolfson
    ArticleOpen Access
  • Fluorogenic RNA aptamers have previously been developed to enhance RNA imaging. We determined the tertiary complex structures of a newly discovered Clivia aptamer, which exhibits a small size and a large Stokes shift. Structural insights into the fluorescence activation mechanism of Clivia build a strong foundation for its efficient use in RNA imaging.

    Research Briefing
  • Toxic small alarmone synthetase (toxSAS) enzymes are toxic effectors of certain toxin–antitoxin modules, involved in phage defense and secretion systems. Here the authors establish the mechanism underlying toxSAS inhibition by structured antitoxins and reveal the connection between neutralization strategy and substrate specificity.

    • Lucia Dominguez-Molina
    • Tatsuaki Kurata
    • Abel Garcia-Pino
    ArticleOpen Access
  • To understand the complex dynamics and diverse functions of RNA, robust technologies for labeling and imaging RNA are highly desirable. A newly developed green fluorescent aptamer named Okra enables the imaging of mRNA dynamics in living cells.

    • Dhrisya Sathyan
    • Murat Sunbul
    News & Views
  • Enediyne natural products are potent antitumor antibiotics but the biosynthesis of their 1,5-diyne-3-ene core has remained enigmatic for decades. Here a diiodotetrayne is reported as a universal enediyne biosynthetic intermediate of this core, obtained upon cryptic iodination.

    • Chun Gui
    • Edward Kalkreuter
    • Ben Shen
  • A de novo-designed protein that precisely assembles a chlorophyll dimer has been developed. The design matches the conformation of the native ‘special pair’ of chlorophylls that functions as the primary electron donor in natural photosynthetic reaction centers. In the designed protein, excitonically coupled chlorophylls participate in energy transfer. The proteins were also redesigned to assemble into 24-chlorophyll nanocages.

    • Nathan M. Ennist
    • Shunzhi Wang
    • David Baker
    ArticleOpen Access
  • 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.

    Research Briefing
  • 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.

    • Hanlun Jiang
    • Kevin M. Jude
    • David Baker
    ArticleOpen Access
  • 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.

    • Kaiyi Huang
    • Qianqian Song
    • Aiming Ren
    ArticleOpen Access
  • 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.

    • Aaron Petruzzella
    • Marine Bruand
    • Elisa Oricchio
  • 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.

    • Tong Lan
    • Bryan C. Dickinson
    News & Views
  • 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.

    • Delia Preti
    • Valentina Albanese
    • Peggy Carla Raffaella Marconi
    News & Views
  • 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.

    • Austin J. Graham
    • Gina Partipilo
    • Benjamin K. Keitz
  • 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.

    • Shaoshuai Xie
    • Gang Li
    News & Views