Peptide-drug conjugates (PDCs) have emerged as a promising modality in precision oncology, enabling targeted delivery of cytotoxic payloads while minimizing off-target toxicity. The integration of covalent warheads, such as those based on sulfur(VI) fluoride exchange (SuFEx) chemistry, enhances drug-target residence time and tumor accumulation. However, existing screening methods for covalent peptide (CP) libraries require post-translational warhead conjugation, limiting throughput. Here, we present an integrated mRNA display platform that incorporates covalent warheads during ribosomal synthesis, enabling efficient screening of ultra-diverse covalent macrocyclic peptide libraries (>10¹³ variants). This approach, using site-specific incorporation of N-chloroacetyl-d-phenylalanine and fluorosulfate-l-tyrosine, accelerated the discovery of irreversibly binding (K _i = 3.58 μmol/L) Nectin-4-targeting peptide CP-N1-N₃ via proximity-triggered SuFEx. The peptide was further conjugated to cytotoxic payloads, yielding the covalent PDC CP-N1-MMAE with potent cytotoxicity (IC₅₀ ≈ 43 nmol/L) against MDA-MB-468 cells. This platform establishes a new paradigm for precision covalent drug discovery.

Objective: To explore the occurrence of cognitive impairment in Chinese heart failure (HF) patients and it's impact on prognosis. Methods: In this prospective observational study, a total of 990 HF patients were enrolled from 24 hospitals in China during December 2012 to November 2014. All patients were administrated with the interview-format Montreal Cognitive Assessment (MoCA), according to which they were divided into MoCA<26 (with cognitive impairment) group and MoCA≥26 (without cognitive impairment) group. Baseline data were collected and a 1-year follow up was carried out. Univariate and multivariate logistic or Cox regression were performed for 1-year outcomes. Results: Cognitive impairment was evidenced in 628 patients (63.4%) and they were more likely to be older, female, and with higher proportion of New York Heart Association(NYHA) class Ⅲ-Ⅳ, chronic obstructive pulmonary disease (COPD), ischemic heart disease, while body mass index (BMI), education level, and medical insurance rate were lower (all P<0.05) as compared to patients in MoCA≥26 group. The rate of percutaneous intervention, device implantation, cardiac surgery and evidence-based medications were significantly lower in MoCA<26 group than in MoCA≥26 group (all P<0.05). During the 1-year follow up, patients in the MoCA<26 group had higher all-cause mortality (10.2%(64/628) vs. 2.2%(8/362), P<0.01), cardiovascular mortality (5.9%(37/628) vs. 0.8%(3/362), P<0.01) and major adverse cardiac and cerebrovascular events (MACCE) (9.6%(60/628) vs. 2.5%(8/362), P<0.01) than patients in the MoCA≥26 group. In univariate regression, MoCA<26 was associated with increased all-cause mortality (HR(95%CI):4.739(2.272-9.885), P<0.01), cardiovascular mortality (HR(95%CI):7.258(2.237-23.548), P=0.001) and MACCE (OR(95%CI):4.143(2.031-8.453), P<0.01). After adjustment by multivariate regression, MoCA<26 was indicated as an independent risk factor for all-cause mortality (HR(95%CI): 6.387(2.533-16.104), P<0.01), cardiovascular mortality (HR(95%CI): 10.848(2.586-45.506), P=0.001) and MACCE (OR(95%CI): 4.081(1.299-12.816), P=0.016), while not for re-hospitalization for HF (OR(95%CI):1.010(0.700-1.457), P=0.957). Conclusions Cognitive impairment is common in HF patients,and it is an independent prognostic factor for 1-year outcomes. Routine cognitive function assessment and active intervention are thus recommended for HF patients.

Adenomatous Polyposis Coli Protein ; chemistry ; metabolism ; Amino Acid Sequence ; Chromatography, High Pressure Liquid ; HeLa Cells ; Humans ; Kinesin ; chemistry ; metabolism ; Microtubule-Associated Proteins ; chemistry ; metabolism ; Microtubules ; metabolism ; Molecular Sequence Data ; Phosphopeptides ; analysis ; Phosphorylation ; Protein Multimerization ; Tandem Mass Spectrometry