Androgen receptor, a possible anti-infective therapy target and a potent immune respondent in SARS-CoV-2 spike binding: a computational approach.

BACKGROUND: Although androgen in gender disparity of COVID-19 has been implied, no direct link has been provided. RESEARCH DESIGN AND METHODS: Here, we applied AlphaFold multimer, network and single cells database analyses to highlight specificity of Androgen receptor (AR) against spike receptor binding protein (RBD) of SARS-CoV-2. RESULTS: LXXL motifs in spike RBD are essential for AR binding. RBD LXXA mutation complex with the AR depicting slightly reduced binding energy, as LXXLL motif usually mediates nuclear receptor binding to coregulators. Moreover, AR preferred to bind a LYRL motif in specificity and interaction interface, and showed reduced affinity against Omicron compared to other variants (alpha, beta, gamma, and delta). Importantly, RBD LYRL motif is a conserved antigenic epitope (9 residues) for T-cell response. Network analysis of AR-related genes against COVID-19 database showed T-cell signaling regulation, and CD8+ T-cell spatial location in AR+ single cells, which is consistent with the AR binding motif LYRL in epitope function. CONCLUSIONS: We provided the potent mechanisms of AR binding to RBD linking to immune response and vaccination shift. AR could be an anti-infective therapy target for anti-Omicron new lineages.

A protein coupling and molecular simulation analysis of the clinical mutants of androgen receptor revealed a higher binding for Leupaxin, to increase the prostate cancer invasion and motility.

Recently a novel coactivator, Leupaxin (LPXN), has been reported to interact with Androgen receptor (AR) and play a significant role in the invasion and progression of prostate cancer. The interaction between AR and LPXN occurs in a ligand-dependent manner and has been reported that the LIM domain in the Leupaxin interacts with the LDB (ligand-binding domain) domain AR. However, no detailed study is available on how the LPXN interacts with AR and increases the (prostate cancer) PCa progression. Considering the importance of the novel co-activator, LPXN, the current study also uses state-of-the-art methods to provide atomic-level insights into the binding of AR and LPXN and the impact of the most frequent clinical mutations H874Y, T877A, and T877S on the binding and function of LPXN. Protein coupling analysis revealed that the three mutants favour the robust binding of LPXN than the wild type by altering the hydrogen bonding network. Further understanding of the binding variations was explored through dissociation constant prediction which demonstrated similar reports as the docking results. A molecular simulation approaches further revealed the dynamic features which reported variations in the dynamics stability, protein packing, hydrogen bonding network, and residues flexibility index. Furthermore, we also assessed the protein motion and free energy landscape which also demonstrated variations in the internal dynamics. The binding free energy calculation revealed -32.95 ± 0.17 kcal/mol for the wild type, for H874Y the total binding energy (BFE) was -36.69 ± 0.11 kcal/mol, for T877A the BFE was calculated to be -38.78 ± 0.17 kcal/mol while for T877S the BFE -41.16 ± 0.12 kcal/mol. This shows that the binding of LPXN is increased by these mutations which consequently increase the PCa invasion and motility. In conclusion, the current study helps in understanding the protein networks and particular the coupling of AR-LPXN in prostate cancer and is of great interest in deciphering the molecular mechanism of disease and therapeutics developments.

Targeting the androgen receptor signaling pathway in advanced prostate cancer.

PURPOSE: This article summarizes current androgen receptor (AR)-directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC). SUMMARY: PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone-releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR gene overexpression, and mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism, possess a higher affinity for AR, and are postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects. CONCLUSION: Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.

Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.

BACKGROUND: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. METHODS: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. FINDINGS: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). INTERPRETATION: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. FUNDING: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.

Covid-19 pathogenesis in prostatic cancer and TMPRSS2-ERG regulatory genetic pathway.

Members of Coronaviridae family have been the source of respiratory illnesses. The outbreak of SARS-CoV-2 that produced a severe lung disease in afflicted patients in China and other countries was the reason for the incredible attention paid toward this viral infection. It is known that SARS-CoV-2 is dependent on TMPRSS2 activity for entrance and subsequent infection of the host cells and TMPRSS2 is a host cell molecule that is important for the spread of viruses such as coronaviruses. Different factors can increase the risk of prostate cancer, including older age, a family history of the disease. Androgen receptor (AR) initiates a transcriptional cascade which plays a serious role in both normal and malignant prostate tissues. TMPRSS2 protein is highly expressed in prostate secretory epithelial cells, and its expression is dependent on androgen signals. One of the molecular signs of prostate cancer is TMPRSS2-ERG gene fusion. In TMPRSS2-ERG-positive prostate cancers different patterns of changed gene expression can be detected. The possible molecular relation between fusion positive prostate cancer patients and the increased risk of lethal respiratory viral infections especially SARS-CoV-2 can candidate TMPRSS2 as an attractive drug target. The studies show that some molecules such as nicotinamide, PARP1, ETS and IL-1R can be studied deeper in order to control SARS-CoV-2 infection especially in prostate cancer patients. This review attempts to investigate the possible relation between the gene expression pattern that is produced through TMPRSS2-ERG fusion positive prostate cancer and the possible influence of these fluctuations on the pathogenesis and development of viral infections such as SARS-CoV-2.

Assessing COVID-19 susceptibility through analysis of the genetic and epigenetic diversity of ACE2-mediated SARS-CoV-2 entry.

There is considerable variation in disease course among individuals infected with SARS-CoV-2. Many of them do not exhibit any symptoms, while some others proceed to develop COVID-19; however, severity of COVID-19 symptoms greatly differs among individuals. Focusing on the early events related to SARS-CoV-2 entry to cells through the ACE2 pathway, we describe how variability in (epi)genetic factors can conceivably explain variability in disease course. We specifically focus on variations in ACE2, TMPRSS2 and FURIN genes, as central components for SARS-CoV-2 infection, and on other molecules that modulate their expression such as CALM, ADAM-17, AR and ESRs. We propose a genetic classifier for predicting SARS-CoV-2 infectivity potential as a preliminary tool for identifying the at-risk-population. This tool can serve as a dynamic scaffold being updated and adapted to validated (epi)genetic data. Overall, the proposed approach holds potential for better personalization of COVID-19 handling.

Smoking-Mediated Upregulation of the Androgen Pathway Leads to Increased SARS-CoV-2 Susceptibility.

The COVID-19 pandemic is marked by a wide range of clinical disease courses, ranging from asymptomatic to deadly. There have been many studies seeking to explore the correlations between COVID-19 clinical outcomes and various clinical variables, including age, sex, race, underlying medical problems, and social habits. In particular, the relationship between smoking and COVID-19 outcome is controversial, with multiple conflicting reports in the current literature. In this study, we aim to analyze how smoking may affect the SARS-CoV-2 infection rate. We analyzed sequencing data from lung and oral epithelial samples obtained from The Cancer Genome Atlas (TCGA). We found that the receptor and transmembrane protease necessary for SARS-CoV-2 entry into host cells, ACE2 and TMPRSS2, respectively, were upregulated in smoking samples from both lung and oral epithelial tissue. We then explored the mechanistic hypothesis that smoking may upregulate ACE2 expression through the upregulation of the androgen pathway. ACE2 and TMPRSS2 upregulation were both correlated to androgen pathway enrichment and the specific upregulation of central pathway regulatory genes. These data provide a potential model for the increased susceptibility of smoking patients to COVID-19 and encourage further exploration into the androgen and tobacco upregulation of ACE2 to understand the potential clinical ramifications.