Kymera Therapeutics

Oral lichen planus (OLP), known as a common and chronic mucosal inflammatory disease. Due to its potential for cancerous transformation, this disease has long been a subject of significant concern. Its pathogenesis is that an unknown antigen activates oral keratinocytes and antigen-presenting cells (APCs) in the epithelium, leading to a T cell-mediated immune response. This study investigates the regulatory role of HIF-1α transcription factor and the potential role of autophagy in a simulated OLP inflammatory cell model. In this study, by comparing the control group with the model group, we observed a notable up-regulation of HIF1A mRNA expression. Additionally, both the autophagy marker protein LC3-II and its substrate p62 exhibited abnormal accumulation, suggesting that autophagy is impaired at the lysosomal degradation stage. Furthermore, mechanistic studies have shown that HIF-1α leads to dysfunction of the autophagy-lysosomal pathway by inhibiting the expression of lysosomal-related genes, while knockdown of HIF-1α alleviates the disruption of autophagic and promotes the improvement of cell activity. In experiments with C. elegans, stimulation with Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) shortens worms' lifespan, but knocking down the hif-1 gene reverses this effect. Similarly, deletion of the key autophagy genes bec-1 and lgg-1 reduces worm survival rates. Results indicate that HIF-1α plays a vital role in regulating autophagy-lysosomal function and cellular homeostasis. In summary, the excessively high expression of HIF-1α aggravates cellular and systemic damage by impairing autophagy-lysosomal function in OLP. Conversely, the targeted inhibition of HIF-1α restores autophagy function, suggesting a potential therapeutic strategy.

Therapeutic strategies increasingly leverage drug combinations, yet preclinical drug synergy frameworks often hinder, rather than accelerate, the clinical translation of medicinal combinations. To modernize the field of drug combination discovery, a multidisciplinary group of practitioners collaborated to distill three key observations underlying successful and failed drug combinations in oncology. These observations are that (1) activity, not synergy, is the primary determinant of a combination's clinical success; (2) synergistic combinations, without disease specificity, commonly fail due to toxicity; and (3) antagonistic combinations are an important and understudied means of improving clinical outcomes. We support the validity of these observations with a mixture of theory, reanalysis of public databases, and review of the literature. Together, these observations argue for a paradigm shift in how preclinical drug combination studies are designed and interpreted to better align with the clinical goals of discovering safe and effective combination therapies.

Multiple spillovers of porcine deltacoronavirus (PDCoV) into humans in Haiti highlight its zoonotic potential and the need for targeted interventions. No approved vaccines or therapeutics are available for use in humans against any DCoVs. Here, we report the de novo design of PDCoV miniprotein inhibitors (aka minibinders, MBs) and show that one of them, MB11, binds with picomolar affinity to the PDCoV receptor-binding domain (RBD). MB11 potently inhibits PDCoV, outcompeting monoclonal antibodies, and cross-reacts with and broadly neutralizes a panel of distantly related DCoVs. We determined a cryoelectron microscopy structure of MB11 bound to the PDCoV RBD which reveals the molecular basis of broad DCoV neutralization through interference with host receptor engagement. Deep mutational scanning of the PDCoV RBD reveals that MB11 has a high barrier to viral escape with only few mutations mediating escape without dampening APN receptor binding. MB11 resists stringent biochemical stresses, including high temperature, low pH, and proteolysis, which may enable delivery to various tissues for viral inhibition. This work delineates a prime candidate for clinical evaluation against PDCoV infection and for pandemic preparedness.

Zinc-finger antiviral protein (ZAP)-mediated RNA decay (ZMD) restricts the replication of viruses containing CpG dinucleotide clusters. However, why ZAP isoforms differ in antiviral activity and how they recruit cofactors to mediate RNA decay is unclear. Therefore, we determined the ordered events of the ZMD pathway. The long ZAP isoform preferentially binds viral RNA and has distinct binding motifs compared to the short isoform. The endoribonuclease KHNYN then cleaves viral RNA at positions of ZAP binding. The 5' cleavage fragment undergoes TUT4/TUT7-mediated 3' uridylation and degradation by DIS3L2. The 3' cleavage fragment is degraded by XRN1. ZAP and TRIM25 interact with KHNYN, TUT7, DIS3L2, and XRN1 in an RNase-resistant manner. Viral infection promotes the interaction between TRIM25 with these enzymes, leading to viral RNA decay while also decreasing the abundance of cellular transcripts. Overall, the long isoform of ZAP recruits key enzymes to assemble an RNA decay complex on viral RNA.

Ubiquitin-proteasome is a conserved mechanism that regulates cellular responses and disease resistance in plants. However, the regulatory role of ubiquitin-proteasome in the pathogenicity of "Candidatus Liberibacter asiaticus" (CLas), the causal agent of citrus huanglongbing (HLB), one of the most serious citrus diseases, remains poorly defined. In this study, we demonstrated that CLIBASIA_04250 (SDE4250) suppresses 26S proteasome activity in citrus, leading to a reduction in salicylic acid (SA) levels and downregulation of SA-responsive genes. Further investigation revealed that SDE4250 specifically targets the citrus 26S proteasome non-ATPase regulatory subunit 4 homologue (CsRPN10) and enhances its degradation via the 26S proteasome pathway. Moreover, overexpression of CsRPN10 inhibited CLas proliferation in citrus hairy roots, which was accompanied by a significant accumulation of SA content and upregulation of related defence genes. Collectively, our findings indicate that SDE4250 targets the citrus 26S proteasome to disrupt SA-mediated citrus immunity.

Osteoarthritis (OA) is a degenerative joint condition mostly affecting the knees characterized by cartilage degradation, synovial inflammation, and chronic pain, with limited effective treatments with minimal side effects. Traditional, complementary, and integrative medicine (TCIM), such as numerous medicinal plants, acupuncture, and folk herbalism, among others, have been historically used to treat symptoms associated with OA, which include joint pain, stiffness, and inflammation. Several herbs and their bioactive constituents have shown potential to modulate key inflammatory pathways like the NLRP3 inflammasome, which is an important regulator of innate immune responses in OA pathophysiology. This review aims to investigate the underlying mechanisms and potential of TCIM to alleviate OA-related pain by modulating the NLRP3 inflammasome. A comprehensive literature search across multiple databases, including PubMed, Cochrane Library, Embase, Google Scholar, Scopus, and Web of Science by using a set of MESH and relevant keywords like "NLRP3", "TCIM", "OA", and "Animal" for articles published from January 2000 to August 2024. Twenty-two in vivo studies met the inclusion criteria for the systematic review, and 21 studies for the meta-analysis. Across these studies, TCIM interventions consistently reduced NLRP3, IL-1β, IL-18, and Caspase-1 expression compared with OA controls. Pooled effects were consistently moderate-to-large across all molecular, with low between-study heterogeneity (I² ≈ 0%). Subgroup analyses by OA model, intervention type, and species indicated broadly similar directions of effect. TCIM shows potential therapeutic approaches for managing OA-related pain by targeting the NLRP3 inflammasome in preclinical OA models. Further research should investigate the clinical translation of these findings to address the unmet need for effective analgesics in OA.