Papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro or Mpro) are viral enzymes essential for the replication of SARS-CoV-2, the virus causing coronavirus disease of 2019 (COVID-19) infection. While 3CLpro has been the main target of many potential antivirals including nirmatrelvir (active ingredient of Paxlovid), PLpro has proven to be more challenging to target and only a handful of inhibitors have been disclosed. However, PLpro inhibitors would enrich the therapeutic arsenal against COVID-19 resistant strains to 3CLpro inhibitors and in future coronavirus pandemics. Combining our experience with 3CLpro covalent inhibitors with our expertise in structure-based covalent drug discovery, we rationally designed PLpro inhibitors achieving a maximum potency (IC50) of 13 μM through fusion of GRL0617 and VIR-251 PLpro inhibitors. In parallel, we launched an integrated large scale virtual screening/experimental approach, identifying four novel chemical series active at micromolar concentrations against PLpro. We report herein our investigations including rational design, virtual screening, synthesis of selected structures and in vitro assays leading to novel PLpro inhibitors. Surprisingly, these two very distinct approaches led to structures with similar features.

Protein design enables the creation of novel structures and functions beyond those found in nature, with recent progress accelerated by computational modeling and machine learning. However, many automated methods act as black boxes, limiting mechanistic insight. Here we highlight the continuing importance of rational protein design, defined as an approach rooted in physical principles, chemical intuition, and sequence-structure-function relationships. We outline three complementary strategies: backbone-first, sequence-first, and function-first, which provide interpretable design frameworks and enable robust scaffold generation, motif incorporation, and functional engineering. Looking forward, we argue that hybrid workflows combining rational principles with machine learning offer the most promising route to dynamic, explainable, and generalizable protein design.

Rational design of dual PB2/JAK2 inhibitors achieving balanced antiviral and host-directed immunomodulatory effects.

Rational design of novel procaspase-3 activators for the targeted therapy of triple-negative breast cancer.

Zn(II)-adjuvanted imidazole-based lipid nanoparticles for potent spleen-targeted mRNA delivery and enhanced immune activation.

A critical review: Rational design and synthesis of high-performance Fe/N/C catalysts for PEMFCs based on mechanistic understanding

Rational design and scalable engineering of artificial interphases for lithium metal anodes

Effective management of skin cancer remains challenging due to limited transdermal drug penetration, systemic toxicity, and therapeutic resistance. In this study, 5-fluorouracil (5-FU)-loaded lipid-polymer hybrid nanoparticles (LPHNPs) were rationally engineered as a next-generation nanocarrier system to overcome these barriers. The hybrid design synergistically combines the structural integrity of polymers with the biocompatibility and permeability-enhancing attributes of lipids. Using a central composite design, formulation parameters were optimized to achieve favorable physicochemical characteristics, yielding nanoparticles with a mean diameter of 256.7 nm, a polydispersity index (PDI) of 0.2711, and a positive zeta potential of +25.47 mV, indicative of excellent colloidal stability. In vitro release and ex vivo permeation studies revealed a sustained drug release profile and significantly improved dermal penetration compared to conventional formulations. Moreover, the Hen's egg test-chorioallantoic membrane (HET-CAM) irritation assay confirmed the biocompatibility and reduced irritation potential of the developed system. Overall, the optimized 5-FU-loaded LPHNPs present a promising platform for localized, controlled transdermal chemotherapy, potentially minimizing systemic exposure and improving therapeutic efficacy in skin cancer management.

Single-Atom Catalysts for Urea Electrooxidation: Rational Design, Synthesis Strategies, and Mechanistic Insights

Improving the thermostability, acid tolerance, and catalytic efficiency of Aspergillus terreus feruloyl esterase by rational design

Ratiometric fluorescent sensing of copper (II) by a new covalent organic framework-based platform.

Systematic evaluation and hepatic targeting of a dual-fluorescence icaritin microemulsion: elucidating the protein corona-mediated delivery mechanism.

Proteolysis-targeting Chimeras induce ferroptosis in cancer: From Mechanism to clinical application.

Functionally integrated palindromic hairpin-enabled signal efficient amplification and continuous transduction for one-pot miRNA sensing.

Synergistic design of ionic liquid monomers and MOF-cellulose scaffolds for selective protein recognition in molecularly imprinted materials.

Rational interface design of PtSe2/g-C3N4 layered heterostructures for photocatalytic water-splitting

Approaching lithium-ion-level performance in sodium-ion batteries through rational reaction-zone design

Advances in green technologies for biocatalytic synthesis of chiral compounds: from enzymatic catalysis to multidisciplinary collaborative innovation.

Advances in chromatography for biomacromolecules and bioparticles (2019-2024): Focus on materials and industrial applications.

Structural diversification and selective inhibition of HDAC3: A comprehensive review of inhibitors and degraders.