TAR RNA selective targeting ruthenium(II) complexes as HIV-1 reverse transcriptase inhibitors: On exploring structure-activity relationships of multiple positions.

HIV-1 reverse transcriptase (RT) inhibitors play a crucial role in the treatment of HIV by preventing the activity of the enzyme responsible for the replication of the virus. The HIV-1 Tat protein binds to transactivation response (TAR) RNA and recruits host factors to stimulate HIV-1 transcription. We have created a small library consisting of 4 × 6 polypyridyl Ru(II) complexes that selectively bind to TAR RNA, with targeting groups specific to HIV-1 TAR RNA. The molecule design was conducted by introducing hydroxyl or methoxy groups into an established potent TAR binder. The potential TAR binding ability was analysis from nature charge population and electrostatic potential by quantum chemistry calculations. Key modifications were found to be R1 and R3 groups. The most potent and selective TAR RNA binder was a3 with R1 = OH, R2 = H and R3 = Me. Through molecular recognition of hydrogen bonds and electrostatic attraction, they were able to firmly and selectively bind HIV-1 TAR RNA. Furthermore, they efficiently obstructed the contact between TAR RNA and Tat protein, and inhibited the reverse transcription activity of HIV-1 RT. The polypyridyl Ru(II) complexes were chemical and photo-stable, and sensitive and selective spectroscopic responses to TAR RNA. They exhibited little toxicity towards normal cells. Hence, this study might offer significant drug design approaches for researching AIDS and other illnesses associated with RT, including HCV, EBOV, and SARS-CoV-2. Moreover, it could contribute to fundamental research on the interactions of inorganic transition metal complexes with biomolecules.

Bithiophene-Functionalized Infrared Two-Photon Absorption Metal Complexes as Single-Molecule Platforms for Synergistic Photodynamic, Photothermal, and Chemotherapy.

A planar conjugated ligand functionalized with bithiophene and its Ru(II), Os(II), and Ir(III) complexes have been constructed as single-molecule platform for synergistic photodynamic, photothermal, and chemotherapy. The complexes have significant two-photon absorption at 808 nm and remarkable singlet oxygen and superoxide anion production in aqueous solution and cells when exposed to 808 nm infrared irradiation. The most potent Ru(II) complex Ru7 enters tumor cells via the rare macropinocytosis, locates in both nuclei and mitochondria, and regulates DNA-related chemotherapeutic mechanisms intranuclearly including DNA topoisomerase and RNA polymerase inhibition and their synergistic effects with photoactivated apoptosis, ferroptosis and DNA cleavage. Ru7 exhibits high efficacy in vivo for malignant melanoma and cisplatin-resistant non-small cell lung cancer tumors, with a 100 % survival rate of mice, low toxicity to normal cells and low residual rate. Such an infrared two-photon activatable metal complex may contribute to a new generation of single-molecule-based integrated diagnosis and treatment platform to address drug resistance in clinical practice and phototherapy for large, deeply located solid tumors.

Dinuclear osmium complexes as mitochondrion-targeting antitumor photothermal agents in vivo.

Four dinuclear osmium complexes have been constructed for antitumor phototherapy. The most potent Os4 has extremely high photothermal conversion capability under irradiation of an 808 nm low-power laser, targets mitochondria in human melanoma cells without nucleus affinity, and acts as an antitumor photothermal therapy agent in vitro and in vivo.

Correlation of mismatch repair deficiency with clinicopathological features and programmed death-ligand 1 expression in thyroid carcinoma.

BACKGROUND: Mutations in DNA mismatch repair (MMR) genes associated with thyroid carcinoma (TC) have rarely been reported, especially in East Asian populations. METHODS: We examined tumor tissue from a cohort of 241 patients diagnosed with TC between 2008 and 2020. MMR proteins were detected using tissue microarray-based immunohistochemistry in order to identify MMR-protein-deficient (MMR-D) and MMR-protein-intact (MMR-I) tumors. We retrospectively summarized the clinicopathologic characteristics of patients with MMR-D TC, measured the expression of PD-L1, and recorded overall survival (OS) and other clinical outcomes. RESULTS: In our cohort, there were 18 (7.5%) MMR-D (MLH1, MSH2, MSH6, and PMS2) patients, including 12 with papillary TC (PTC) (6.7%), 2 with poorly differentiated TC (PDTC) (4.7%), and 4 with anaplastic TC (ATC) (22.2%). Half of them (9/18) showed a specific deletion in MSH6, and 6 of them also carried variants in the MSH6 and PMS2 gene. Survival was significantly better in patients with MMR-D ATC than in those with MMR-I tumors (p = 0.033). Four of the 18 MMR-D patients (22%) were found to be PD-L1 positive. Their OS was much shorter than that of PD-L1-negative patients. CONCLUSIONS: MMR-D and PD-L1 positivity appear to be associated with clinicopathological characteristics and prognosis in TC. The results indicate that MMR status may have important prognostic significance in TC. Therefore, immune checkpoint inhibitors that target the PD-1/PD-L1 pathway may be a treatment option for TCs.