DTX3L-mediated TIRR nuclear export and degradation regulates DNA repair pathway choice and PARP inhibitor sensitivity.

53BP1 plays an important role in DNA double-strand break (DSB) repair and this activity is negatively regulated by its interaction with Tudor interacting repair regulator (TIRR). However, how the TIRR-53BP1 repair axis is regulated in response to DNA damage remains elusive. Here, we demonstrate that TIRR is translocated to the cytoplasm and degraded upon DNA damage.

Discovery of a peptide proteolysis-targeting chimera (PROTAC) drug of p300 for prostate cancer therapy.

Background: The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC).

A Top-Down Design Approach for Generating a Peptide PROTAC Drug Targeting Androgen Receptor for Androgenetic Alopecia Therapy.

While large-scale artificial intelligence (AI) models for protein structure prediction and design are advancing rapidly, the translation of deep learning models for practical macromolecular drug development remains limited. This investigation aims to bridge this gap by combining cutting-edge methodologies to create a novel peptide-based PROTAC drug development paradigm. Using ProteinMPNN and RFdiffusion, we identified binding peptides for androgen receptor (AR) and Von Hippel-Lindau (VHL), followed by computational modeling with Alphafold2-multimer and ZDOCK to predict spatial interrelationships.

Development of a PAK4-targeting PROTAC for renal carcinoma therapy: concurrent inhibition of cancer cell proliferation and enhancement of immune cell response.

Background: Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment.

CK2-dependent degradation of CBX3 dictates replication fork stalling and PARP inhibitor sensitivity.

DNA replication is a vulnerable cellular process, and its deregulation leads to genomic instability. Here, we demonstrate that chromobox protein homolog 3 (CBX3) binds replication protein A 32-kDa subunit (RPA2) and regulates RPA2 retention at stalled replication forks. CBX3 is recruited to stalled replication forks by RPA2 and inhibits ring finger and WD repeat domain 3 (RFWD3)-facilitated replication restart.

Development of a Double-Stapled Peptide Stabilizing Both α-Helix and β-Sheet Structures for Degrading Transcription Factor AR-V7.

Peptide drugs offer distinct advantages in therapeutics; however, their limited stability and membrane penetration abilities hinder their widespread application. One strategy to overcome these challenges is the hydrocarbon peptide stapling technique, which addresses issues such as poor conformational stability, weak proteolytic resistance, and limited membrane permeability. Nonetheless, while peptide stapling has successfully stabilized α-helical peptides, it has shown limited applicability for most β-sheet peptide motifs.

TRABID overexpression enables synthetic lethality to PARP inhibitor via prolonging 53BP1 retention at double-strand breaks.

53BP1 promotes nonhomologous end joining (NHEJ) over homologous recombination (HR) repair by mediating inactivation of DNA end resection. Ubiquitination plays an important role in regulating dissociation of 53BP1 from DNA double-strand breaks (DSBs). However, how this process is regulated remains poorly understood.

EZH2-regulated immune risk score prognostic model predicts outcome of clear cell renal cell carcinoma.

Background: The enhancer of zeste homolog 2 (EZH2) plays an important role in the tumor microenvironment (TME), and EZH2 in shaping the epigenetic landscape of CD8 T cell fate and function, with a particular emphasis on cancer. Here, high EZH2 expression always leads to less CD8 T cell infiltration. However, clear cell renal cell carcinoma (ccRCC) is reportedly a "hot" tumor, with contradictory high EZH2 expression.

De Novo Design of an Androgen Receptor DNA Binding Domain-Targeted peptide PROTAC for Prostate Cancer Therapy.

Androgen receptor splice variant-7 (AR-V7), one of the major driving factors, is the most attractive drug target in castration-resistant prostate cancer (CRPC). Currently, no available drugs efficiently target AR-V7 in clinical practice. The DNA binding domain (DBD) is indispensable for the transcriptional activity of AR full length and AR splice variants, including AR-V7.

Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors.

Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors.

Current Landscape and Future Perspective of Oxazolidinone Scaffolds Containing Antibacterial Drugs.

The widespread use of antibiotics has made the problem of bacterial resistance increasingly serious, and the study of new drug-resistant bacteria has become the main direction of antibacterial drug research. Among antibiotics, the fully synthetic oxazolidinone antibacterial drugs linezolid and tedizolid have been successfully marketed and have achieved good clinical treatment effects. Oxazolidinone antibacterial drugs have good pharmacokinetic and pharmacodynamic characteristics and unique antibacterial mechanisms, and resistant bacteria are sensitive to them.

2-((3,5-Dinitrobenzyl)thio)quinazolinones: Potent Antimycobacterial Agents Activated by Deazaflavin (F)-Dependent Nitroreductase (Ddn).

Swapping the substituents in positions 2 and 4 of the previously synthesized but yet undisclosed 5-cyano-4-(methylthio)-2-arylpyrimidin-6-ones , ring closure, and further optimization led to the identification of the potent antitubercular 2-thio-substituted quinazolinone . Structure-activity relationship (SAR) studies indicated a crucial role for both -nitro substituents for antitubercular activity, while the introduction of polar substituents on the quinazolinone core allowed reduction of bovine serum albumin (BSA) binding (, ). While most of the tested quinazolinones exhibited no cytotoxicity against MRC-5, the most potent compound was found to be mutagenic via the Ames test.

Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents.

As the last enzyme in nucleotide synthesis as precursors for DNA replication, thymidylate kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake.

The development of Coronavirus 3C-Like protease (3CL) inhibitors from 2010 to 2020.

This review fully describes the coronavirus 3CL peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CL inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CL Cys145 residue and thereby achieve irreversible inhibition effects, whereas nonpeptidic small molecule inhibitors mainly interact with residues in the S1', S1, S2 and S4 pockets via hydrogen bonds, hydrophobic bonds and van der Waals forces. Based on the emerging PROTAC technology and the existing 3CL inhibitors, 3CL PROTAC degraders are hypothesised to be next-generation anti-coronavirus drugs.

1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors.

A series of TMPK (TMPK) inhibitors based on a reported compound were synthesized and evaluated for their capacity to inhibit TMPK catalytic activity and the growth of a virulent strain (H37Rv). Modifications of the scaffold of failed to afford substantial improvements in TMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of resulted in compound with improved TMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold).

1-(Piperidin-3-yl)thymine amides as inhibitors of thymidylate kinase.

A series of readily accessible 1-(piperidin-3-yl)thymine amides was designed, synthesised and evaluated as TMPK (TMPK) inhibitors. In line with the modelling results, most inhibitors showed reasonable TMPK inhibitory activity. Compounds and were slightly more potent than the parent compound .

Synthesis and evaluation of 2-cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13β, 28-olide as a potent anti-inflammatory agent for intervention of LPS-induced acute lung injury.

The present study was designed to synthesize 2-Cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13β, 28-olide (1), a lactone derivative of oleanolic acid (OA) and evaluate its anti-inflammatory activity. Compound 1 significantly diminished nitric oxide (NO) production and down-regulated the mRNA expression of iNOS, COX-2, IL-6, IL-1β, and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells.

Preparation, macrophages targeting delivery and anti-inflammatory study of pentapeptide grafted nanostructured lipid carriers.

The targeting ability of pentapeptide (Thr-Lys-Pro-Pro-Arg) grafted nanostructured lipid carriers (Pen-NLCs) to macrophages was investigated in both in vitro and in vivo studies. The results showed the improvement of the anti-inflammatory effect by using this drug delivery system. Firstly, a pentapeptide-polyethylene glycol2000-stearate was synthesized and formulated into Pen-NLCs.

Anti-inflammatory activity of injectable dexamethasone acetate-loaded nanostructured lipid carriers.

This work studied the intravenous injection formulation of nanostructured lipid carriers (NLCs) loaded with dexamethasone acetate (DA), a poorly water-soluble drug. The goal of this study was to design nanoparticles which could improve therapeutic efficacy of DA on inflammations. Based on the optimized results of single-factor screening experiment, DA-loaded NLCs (DA-NLCs) prepared by an emulsification-ultrasound method were found to be relatively uniform in size (178 ± 4 nm) with a negative zeta potential (-38 ± 4 mV).

In vivo biodistribution, anti-inflammatory, and hepatoprotective effects of liver targeting dexamethasone acetate loaded nanostructured lipid carrier system.

We aimed to evaluate whether the enhancement of the liver accumulation and anti-inflammatory activity of dexamethasone acetate (DXMA) could be achieved by incorporating it into nanostructured lipid carrier (NLCs). DXMA-NLCs were prepared using a film dispersion-ultrasonication method and characterized in terms of particle size, PDI, zeta potential, differential scanning calorimetry, drug loading capacity, encapsulation efficiency, and in vitro release. The biodistribution and pharmacokinetics of DXMA-NLCs in mice were significantly different from those of the DXMA solution (DXMA-sol).

Lung-targeting delivery of dexamethasone acetate loaded solid lipid nanoparticles.

The objective of the present study was to develop a novel solid lipid nanoparticle (SLN) for the lung-targeting delivery of dexamethasone acetate (DXM) by intravenous administration. DXM loaded SLN colloidal suspensions were prepared by the high pressure homogenization method. The mean particle size, drug loading capacity and drug entrapment efficiency (EE%) of SLNs were investigated.