A knowledge-based protein-protein interaction inhibition (KPI) pipeline: an insight from drug repositioning for COVID-19 inhibition.

The inhibition of protein-protein interactions (PPIs) by small molecules is an exciting drug discovery strategy. Here, we aimed to develop a pipeline to identify candidate small molecules to inhibit PPIs. Therefore, KPI, a Knowledge-based Protein-Protein Interaction Inhibition pipeline, was introduced to improve the discovery of PPI inhibitors. Then, phytochemicals from a collection of known Middle Eastern antiviral herbs were screened to identify potential inhibitors of key PPIs involved in COVID-19. Here, the following investigations were sequenced: 1) Finding the binding partner and the interface of the proteins in PPIs, 2) Performing the blind ligand-protein inhibition (LPI) simulations, 3) Performing the local LPI simulations, 4) Simulating the interactions of the proteins and their binding partner in the presence and absence of the ligands, and 5) Performing the molecular dynamics simulations. The pharmacophore groups involved in the LPI were also characterized. Aloin, Genistein, Neoglucobrassicin, and Rutin are our new pipeline candidates for inhibiting PPIs involved in COVID-19. We also propose KPI for drug repositioning studies.Communicated by Ramaswamy H. Sarma.

Reverse expression pattern of sirtuin-1 and histone deacetylase-9 in coronary artery disease.

BACKGROUND: SIRT1 and HDAC 9 genes are related to inflammation and may contribute to the pathogenesis of coronary artery disease (CAD). We aimed to evaluate the expression level, methylation profile and polymorphisms of these genes in CAD patients. METHODS: In this study, 50 CAD patients and 50 healthy individuals were recruited. The expression level change was evaluated using the TaqMan Real-Time PCR method. The methylation of genes promoter and genotyping of polymorphisms were evaluated by the HRM. RESULTS: The expression level of SIRT1 was reduced while the HDAC9 expression level showed a significant elevation (p < .001). The SIRT1 gene promoter was hypomethylated and the HDAC9 gene promoter was hypermethylated in CAD patients. Also, CG + GG genotype in SIRT1 and both genotypes in the HDAC9 gene were associated with expression change. CONCLUSIONS: SIRT1 and HDAC9 genes, expression changes can be suggested as a potential biomarker for CAD detection.

Immune Checkpoint Inhibitors in Cancer Therapy.

The discovery of immune checkpoint proteins such as PD-1/PDL-1 and CTLA-4 represents a significant breakthrough in the field of cancer immunotherapy. Therefore, humanized monoclonal antibodies, targeting these immune checkpoint proteins have been utilized successfully in patients with metastatic melanoma, renal cell carcinoma, head and neck cancers and non-small lung cancer. The US FDA has successfully approved three different categories of immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors (Nivolumab, Pembrolizumab, and Cemiplimab), PDL-1 inhibitors (Atezolimumab, Durvalumab and Avelumab), and CTLA-4 inhibitor (Ipilimumab). Unfortunately, not all patients respond favourably to these drugs, highlighting the role of biomarkers such as Tumour mutation burden (TMB), PDL-1 expression, microbiome, hypoxia, interferon-γ, and ECM in predicting responses to ICIs-based immunotherapy. The current study aims to review the literature and updates on ICIs in cancer therapy.

High-throughput analysis of the interactions between viral proteins and host cell RNAs.

RNA-protein interactions of a virus play a major role in the replication of RNA viruses. The replication and transcription of these viruses take place in the cytoplasm of the host cell; hence, there is a probability for the host RNA-viral protein and viral RNA-host protein interactions. The current study applies a high-throughput computational approach, including feature extraction and machine learning methods, to predict the affinity of protein sequences of ten viruses to three categories of RNA sequences. These categories include RNAs involved in the protein-RNA complexes stored in the RCSB database, the human miRNAs deposited at the mirBase database, and the lncRNA deposited in the LNCipedia database. The results show that evolution not only tries to conserve key viral proteins involved in the replication and transcription but also prunes their interaction capability. These proteins with specific interactions do not perturb the host cell through undesired interactions. On the other hand, the hypermutation rate of NSP3 is related to its affinity to host cell RNAs. The Gene Ontology (GO) analysis of the miRNA with affiliation to NSP3 suggests that these miRNAs show strongly significantly enriched GO terms related to the known symptoms of COVID-19. Docking and MD simulation study of the obtained miRNA through high-throughput analysis suggest a non-coding RNA (an RNA antitoxin, ToxI) as a natural aptamer drug candidate for NSP5 inhibition. Finally, a significant interplay of the host RNA-viral protein in the host cell can disrupt the host cell's system by influencing the RNA-dependent processes of the host cells, such as a differential expression in RNA. Furthermore, our results are useful to identify the side effects of mRNA-based vaccines, many of which are caused by the off-label interactions with the human lncRNAs.

Correlation between important genes of mTOR pathway (PI3K and KIT) in Iranian women with sporadic breast cancer.

Background: PI3K/Akt/mTOR pathway is a crucial pathway in the angiogenesis, tumour growth and cell differentiation of several cancers. The PI3K and KIT genes are key genes of this pathway. Previous studies have reported the importance of these genes in the development of gastrointestinal carcinoma, leukaemia, and melanomas. The role of mutations and overexpression of PI3K and KIT genes in breast cancer has been previously proved. This study investigates the correlation between PI3K and KIT gene mutations in sporadic breast cancer. Methods: Multiplex Ligation-dependent Probe Amplification (MLPA) technique was used to determine the Copy Number Variation (CNV) of PI3K and KIT genes in 34 breast cancer tumours and PCR-sequencing was used to detect the mutation in PI3K exons 9 and 20. Results: Our results reported that 27% of patients had CNV of the KIT gene; whereas, 20% and 17.5% of patients, had mutation and CNV in the PI3K gene, respectively. We did not found a significant correlation between the mutations of PI3K and KIT genes. Conclusion: About two-tenth of the patients revealed CNV and lesser than two-tenth indicated mutation in the PI3K gene, whereas one-third of the patients demonstrated CNV in the KIT gene. Thus, administration of the PI3K and KIT gene inhibitor drugs might be proposed to suppress breast cancer in patients with mutation and CNV of each of these individual genes.

Relationship Between PIK3CA Amplification and P110α and CD34 Tissue Expression as Angiogenesis Markers in Iranian Women with Sporadic Breast Cancer.

BACKGROUND AND OBJECTIVE: The PI3K/AKT/mTOR pathway is known to play an important role in regulating angiogenesis both in normal and breast cancer (BC) tissues. PIK3CA amplification was reported in various malignancies, including approximately 10% of BC cases. The aim of this study was to identify the frequency of PIK3CA amplification in Iranian female patients suffering from BC. Additionally, possible association between PIK3CA amplification and P110α expression with microvascular density (MVD) was examined. METHODS: DNA samples were extracted from paraffin embedded tumor tissue blocks and copy number changes were evaluated by MLPA Technique. The results were analyzed by coffalyzer software. The tissue expression of P110α and CD34 was assessed using immunohistochemistry. RESULTS: Ten out of 40 samples (17.5%) showed amplification in PIK3CA gene and 22 out of 40 samples (55%) showed overexpression in P110α. For CD34, from 40 samples, 20 (50%), 15 (37.5%) and 5 (12.5%) had scores 1+, 2+ and 3+, respectively. CONCLUSION: No significant association was detected between gain of PIK3CA copy number and P110α or CD34 tissue expression.