Discovery of Pteridine-7(8H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK).

Bruton's tyrosine kinase (BTK) is an attractive therapeutic target in the treatment of cancer, inflammation, and autoimmune diseases. Covalent and noncovalent BTK inhibitors have been developed, among which covalent BTK inhibitors have shown great clinical efficacy. However, some of them could produce adverse effects, such as diarrhea, rash, and platelet dysfunction, which are associated with the off-target inhibition of ITK and EGFR. In this study, we disclosed a series of pteridine-7(8H)-one derivatives as potent and selective covalent BTK inhibitors, which were optimized from 3z, an EGFR inhibitor previously reported by our group. Among them, compound 24a exhibited great BTK inhibition activity (IC50 = 4.0 nM) and high selectivity in both enzymatic (ITK >250-fold, EGFR >2500-fold) and cellular levels (ITK >227-fold, EGFR 27-fold). In U-937 xenograft models, 24a significantly inhibited tumor growth (TGI = 57.85%) at a 50 mg/kg dosage. Accordingly, 24a is a new BTK inhibitor worthy of further development.

Prise en charge médicale de la récidive du cancer épithélial de l'ovaire: Medical management of recurrent epithelial ovarian cancer.

The panel of therapeutic options available for medical treatment of relapsed ovarian cancer increased over the last years. In late, platinum-sensitive relapse, standard treatment remains platinum-based polychemotherapy. The choice between bevacizumab added to chemotherapy followed by maintenance and inhibitors of poly-(ADP-riboses) polymerases (PARPi) after response to platinum-based therapy should be discussed, taking into account prior treatment, contraindications, and disease characteristics (biology, symptoms…). The addition of bevacizumab at first platinum-sensitive relapse can be considered if it has not been administered in first line, and it is optional (rechallenge) if previously administered (but without Marketing Authorization in this setting). PARPi are indicated for maintenance therapy after response to platinum-based chemotherapy (whatever the treatment line), regardless of BRCA mutational status, in case of no prior administration. Early relapses are associated with poor prognosis and therapeutic options are more limited. They are treated by monochemotherapy without platinum agents, associated with bevacizumab if not administered previously. Beyond first early relapse, there is no standard and inclusion in a clinical trial should be proposed if possible. Several clinical studies assessing associations of immunotherapy and chemotherapy and/or antiangiogenic drugs and/or targeted therapies (such as PARPi) are ongoing in early or late relapse.

RSK Inhibition Induces Apoptosis by Downregulating Protein Synthesis in a Variety of Acute Myeloid Leukemia Cell Lines.

Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1/2 (IDH1/2) mutations drive malignancy in acute myeloid leukemia (AML), which accounts for approximately 40% of AML cases. Treatment with FLT3 or IDH1/2 inhibitors is used for such patients; however, it is not considered for most patients with AML who lack mutations on the respective genes. In this study, p90 ribosomal S6 kinase (RSK) was found to serve as a new therapeutic target in various AMLs with or without FLT3 mutations. BI-D1870, a potent inhibitor of RSK, significantly suppressed the proliferation of AML cell lines, among which three encoded wild-type FLT3 and three contained FLT3 driver mutations, compared with chronic myeloid leukemia K562 cells or other adherent cancer cells. BI-D1870 inhibited protein synthesis by dephosphorylating the p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 in all AML cells except KG-1a cells. Meanwhile, the expression of microtubule-associated protein light chain 3B-I and -II increased in KG-1a cells treated with BI-D1870. BI-D1870 induced caspase-dependent apoptosis in all AML cells, including KG-1a cells. We next investigated the synergistic effect of BI-D1870 with cytarabine, a traditional anticancer drug used in AML. Synergistic effects of BI-D1870 and cytarabine were not observed in any of the cell lines. The findings suggested that BI-D1870 alone exerts an adequate antiproliferative effect on AML with or without FLT3 mutations and serves as a novel AML therapeutic agent.

Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus-1.

BACKGROUND: Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1. METHODS: In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose-escalation cohorts. The primary study objectives included establishing the safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives. RESULTS: A total of 48 individuals were randomly assigned to vesatolimod (n = 36) or placebo (n = 12). Vesatolimod was generally well tolerated, with no study drug-related serious adverse events or adverse events leading to study drug discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups, compared to placebo.Vesatolimod plasma exposures increased dose proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours after receipt of a 6 mg dose were >3.9-fold higher for interferon gamma-induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RA), interferon-inducible T-cell alpha chemoattractant (ITAC) when compared to baseline values. CONCLUSIONS: Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation was observed at doses above 4 mg, providing rationale for future combination trials in people living with HIV. CLINICAL TRIALS REGISTRATION: NCT02858401.

A TLR7 agonist activates bovine Th1 response and exerts antiviral activity against bovine leukemia virus.

Bovine leukemia virus (BLV) infection is a bovine chronic infection caused by BLV, a member of the genus Deltaretrovirus. In this study, we examined the immunomodulatory effects of GS-9620, a toll-like receptor (TLR) 7 agonist, in cattle (Bos taurus) and its therapeutic potential for treating BLV infection. GS-9620 induced cytokine production in peripheral blood mononuclear cells (PBMCs) as well as CD80 expression in CD11c+ cells and increased CD69 and interferon (IFN)-γ expressions in T cells. Removing CD11c+ cells from PBMCs decreased CD69 expression in T cells in the presence of GS-9620. These results suggest that TLR7 agonism promotes T-cell activation via CD11c+ cells. Analyses using PBMCs from BLV-infected cattle revealed that TLR7 expression in CD11c+ cells was upregulated during late-stage BLV infection. Furthermore, GS-9620 increased IFN-γ and TNF-α production and inhibited syncytium formation in vitro, suggesting that GS-9620 may be used to treat BLV infection.

PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance.

A significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Here we perform whole exome sequencing and gene expression analysis of matched primary breast tumours and bone metastasis-derived patient-derived xenografts (PDX). Transcriptomic analyses reveal enrichment of the G2/M checkpoint and up-regulation of Polo-like kinase 1 (PLK1) in PDX. PLK1 inhibition results in tumour shrinkage in highly proliferating CCND1-driven PDX, including different RB-positive PDX with acquired palbociclib resistance. Mechanistic studies in endocrine resistant cell lines, suggest an ER-independent function of PLK1 in regulating cell proliferation. Finally, in two independent clinical cohorts of ER positive BC, we find a strong association between high expression of PLK1 and a shorter metastases-free survival and poor response to anastrozole. In conclusion, our findings support clinical development of PLK1 inhibitors in patients with advanced CCND1-driven BC, including patients progressing on palbociclib treatment.

PLK1 Inhibition alleviates transplant-associated obliterative bronchiolitis by suppressing myofibroblast differentiation.

Chronic allograft dysfunction (CAD) resulting from fibrosis is the major limiting factor for long-term survival of lung transplant patients. Myofibroblasts promote fibrosis in multiple organs, including the lungs. In this study, we identified PLK1 as a promoter of myofibroblast differentiation and investigated the mechanism by which its inhibition alleviates transplant-associated obliterative bronchiolitis (OB) during CAD. High-throughput bioinformatic analyses and experiments using the murine heterotopic tracheal transplantation model revealed that PLK1 is upregulated in grafts undergoing CAD as compared with controls, and that inhibiting PLK1 alleviates OB in vivo. Inhibition of PLK1 in vitro reduced expression of the specific myofibroblast differentiation marker α-smooth muscle actin (α-SMA) and decreased phosphorylation of both MEK and ERK. Importantly, we observed a similar phenomenon in human primary fibroblasts. Our results thus highlight PLK1 as a promising therapeutic target for alleviating transplant-associated OB through suppression of TGF-ß1-mediated myofibroblast differentiation.

Activation of HIV-specific CD8+ T-cells from HIV+ donors by vesatolimod.

BACKGROUND: Vesatolimod (VES; GS-9620) is a Toll-like receptor 7 (TLR7) agonist that directly activates human plasmacytoid dendritic cells (pDCs) and B lymphocytes resulting in direct and indirect production of cytokines and immune activation. VES is being evaluated in HIV-1-infected people as part of an HIV remission strategy. Here we investigated the potential of VES to trigger indirect activation of HIV-specific CD8+ T-cells using immune cell cultures derived from HIV+ donors. METHODS: Peripheral blood mononuclear cell (PBMC) cultures derived from HIV+ donors virologically suppressed on stable antiretroviral therapy (n=31) were isolated and treated with VES or vehicle for 24 h. Cells were stained with surface and intracellular fluorescent conjugated antibodies and HIV-specific pentamers, and analysed by flow cytometry. RESULTS: Treatment of PBMCs with VES resulted in all 31 donors demonstrating a concentration dependent increase in CD8+ T-cell activation (CD69+) of up to 88%. Of these donors, 20 of 31 donors displayed a concentration-dependent increase in HIV-specific CD8+ T-cell activation due to VES with a maximum of 20.8%. Intracellular staining was performed in a subset of donors (n=14), 5 of which displayed VES-induced activation of functional HIV-specific CD8+ T-cells as assessed by CD107a and/or tumour necrosis factor (TNF)-α upregulation. CONCLUSIONS: This study demonstrates that VES treatment can induce the activation of functional HIV-specific CD8+ T-cells in donor derived PBMCs. These data support the potential use of VES to activate functional HIV-specific CD8+ T-cells as part of an HIV remission strategy.

BI6727, a polo-like kinase 1 inhibitor with promising efficacy on Burkitt lymphoma cells.

OBJECTIVE: BI6727, an ATP-competitive PLK1 inhibitor, has been shown to cause cell death in multi-tumors. This study aimed to investigate the anti-tumor effect and potential molecular mechanism of BI6727 in human Burkitt lymphoma (BL) cell lines. METHODS: We assessed polo-like kinase 1 (PLK1) expression in BL patient tissues and cells, also investigated the cytotoxic effect using CCK8 assay and flow cytometry. In addition, western blotting and real-time polymerase chain reaction (RT-PCR) assays were used to explore the molecular mechanisms of BI6727 in human BL cell lines. RESULTS: PLK1 was overexpressed in BL cells compared with normal cells. The PLK1 inhibitor BI6727 reduced activated PLK1 expression and caused mitotic arrest in BL cells. Additionally, BI6727 suppressed cellular proliferation and induced apoptosis in BL cell lines. BI6727 treatment also decreased C-MYC protein and mRNA expression, blocked the PI3K/AKT/mTOR signaling pathway, and stabilized the FBXW7 protein. CONCLUSIONS: Our findings explained a potential molecular mechanism of BI6727 in BL cells and suggested that BI6727 might be a new therapeutic agent for BL in the future.

PLK1/NF-κB feedforward circuit antagonizes the mono-ADP-ribosyltransferase activity of PARP10 and facilitates HCC progression.

Dysregulation of PARP10 has been implicated in various tumor types and plays a vital role in delaying hepatocellular carcinoma (HCC) progression. However, the mechanisms controlling the expression and activity of PARP10 in HCC remain mostly unknown. The crosstalk between PLK1, PARP10, and NF-κB pathway in HCC was determined by performing different in vitro and in vivo assays, including mass spectrometry, kinase, MARylation, chromatin immunoprecipitation, and luciferase reporter measurements. Functional examination was performed by using small chemical drug, cell culture, and mice HCC models. Correlation between PLK1, NF-κB, and PARP10 expression was determined by analyzing clinical samples of HCC patients with using immunohistochemistry. PLK1, an important regulator for cell mitosis, directly interacts with and phosphorylates PARP10 at T601. PARP10 phosphorylation at T601 significantly decreases its binding to NEMO and disrupts its inhibition to NEMO ubiquitination, thereby enhancing the transcription activity of NF-κB toward multiple target genes and promoting HCC development. In turn, NF-κB transcriptionally inhibits the PARP10 promoter activity and leads to its downregulation in HCC. Interestingly, PLK1 is mono-ADP-ribosylated by PARP10 and the MARylation of PLK1 significantly inhibits its kinase activity and oncogenic function in HCC. Clinically, the expression levels of PLK1 and phosphor-p65 show an inverse correlation with PARP10 expression in human HCC tissues. These findings are the first to uncover a PLK1/PARP10/NF-κB signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with NF-κB antagonists, as potential effective therapeutics for PARP10-expressing HCC.

TGFß Inhibition Stimulates Collagen Maturation to Enhance Bone Repair and Fracture Resistance in a Murine Myeloma Model.

Multiple myeloma is a plasma cell malignancy that causes debilitating bone disease and fractures, in which TGFß plays a central role. Current treatments do not repair existing damage and fractures remain a common occurrence. We developed a novel low tumor phase murine model mimicking the plateau phase in patients as we hypothesized this would be an ideal time to treat with a bone anabolic. Using in vivo µCT we show substantial and rapid bone lesion repair (and prevention) driven by SD-208 (TGFß receptor I kinase inhibitor) and chemotherapy (bortezomib and lenalidomide) in mice with human U266-GFP-luc myeloma. We discovered that lesion repair occurred via an intramembranous fracture repair-like mechanism and that SD-208 enhanced collagen matrix maturation to significantly improve fracture resistance. Lesion healing was associated with VEGFA expression in woven bone, reduced osteocyte-derived PTHrP, increased osteoblasts, decreased osteoclasts, and lower serum tartrate-resistant acid phosphatase 5b (TRACP-5b). SD-208 also completely prevented bone lesion development in mice with aggressive JJN3 tumors, and was more effective than an anti-TGFß neutralizing antibody (1D11). We also discovered that SD-208 promoted osteoblastic differentiation (and overcame the TGFß-induced block in osteoblastogenesis) in myeloma patient bone marrow stromal cells in vitro, comparable to normal donors. The improved bone quality and fracture-resistance with SD-208 provides incentive for clinical translation to improve myeloma patient quality of life by reducing fracture risk and fatality. © 2019 American Society for Bone and Mineral Research.

Sorafenib-loaded hydroxyethyl starch-TG100-115 micelles for the treatment of liver cancer based on synergistic treatment.

Tumor microenvironment is closely related to the occurrence and development of liver cancer. Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment promoting tumor deterioration and metastasis by inhibiting immune cells. Previous studies showed that PI3Kγ inhibitor could reverse the phenotype of TAMs, relieve immunosuppression and sensitize chemotherapy drugs, suggesting that the combination of PI3Kγ inhibitor and chemotherapeutics is likely to bring new breakthroughs in the treatment of liver cancer. Based on it, this paper builds HES-TG100-115-CDM-PEG micelles with tumor microenvironment responsiveness that simultaneously loaded sorafenib and TG100-115 to synergistically treat liver cancer. Pharmacokinetic study showed that the prepared micelles had longer half-life than that of the free drug solutions, which was favorable for high propensity of extravasation through tumor vascular fenestrations. Under low pH and high α-amylasereductive conditions, micelles could depolymerize quickly due to the sensitivity of bonds and enhance significantly cytotoxic activity against Hep-3B liver cancer cell. Additionally, micelles demonstrated higher levels of antitumor efficiency and better tolerance against nude mouse with Hep-3B cell than the free drug solutions. These findings reveal that HES-TG100-115-CDM-PEG micelles are a promising drug delivery system in clinical comprehensive therapy of liver cancer.

TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremia.

Reduction/elimination of HIV-1 reservoirs that persist despite combination antiretroviral therapy (cART) will likely require induction of viral expression by residual infected cells and enhanced clearance of these cells. TLR7 agonists have potential to mediate these activities. We evaluated immunologic and virologic effects of repeated doses of the TLR7 agonist GS-9620 in SIV-infected rhesus macaques receiving cART, which was initiated at 13 days after infection and was continued for 75 weeks prior to GS-9620 administration. During cART, GS-9620 induced transient upregulation of IFN-stimulated genes in blood and tissues, increases in plasma cytokines, and changes in immune cell population activation and phenotypes but did not result in measurable increases in plasma viremia or viral RNA-to-viral DNA ratio in PBMCs or tissues nor decreases in viral DNA in PBMC or tissues. SIV-specific CD8+ T cell responses, negligible prior to GS-9620 treatment, were not measurably boosted by treatment; a second course of GS-9620 administration overlapping with later cART discontinuation was associated with increased CD8+ T cell responses during viral recrudescence. These results confirm and extend evidence for GS-9620-mediated enhancement of antiviral immune responses in SIV-infected macaques but suggest that GS-9620-mediated viral induction may depend critically on the timing of initiation and duration of cART and resulting characteristics of viral reservoirs.

Patient-reported outcomes in patients chronic viral hepatitis without cirrhosis: The impact of hepatitis B and C viral replication.

BACKGROUND & AIM: Chronic infections with hepatitis B or C (HBV and HCV) are associated with adverse clinical outcomes and patient-reported outcomes (PROs). The aim is to compare PRO scores in patients with chronic HBV and HCV without advanced liver disease before and after suppression/clearance of their infection. METHODS: Patients with HCV and HBV infection prior to initiation of antiviral treatment and after viral suppression/eradication completed PRO questionnaires. RESULTS: We included 132 patients with HBV and 132 matched patients with HCV. Baseline PRO scores were significantly higher in patients with HBV in the domains of Physical Functioning, Role Physical, Bodily Pain, Social Functioning, and Role Emotional of SF-36, SF-6D utility, Emotional and Fatigue domains of CLDQ, Presenteeism and total Work Productivity Impairment of WPAI:SHP in comparison to patients with HCV by 5.8%-13.2% of a PRO score range (all P < 0.05). After viral suppression (HBV DNA < 20 IU/mL after 48 weeks of treatment for HBV) or eradication (SVR-12 for HCV), only Physical Functioning and Role Physical scores remained higher in HBV by 6.7%-9.9%, while other PRO scores became similar between HBV and HCV groups (P > 0.05). The most prominent improvement of PROs in HCV was noted in Vitality, Emotional, Fatigue and Worry domains. In addition, General Health, Worry and Work Productivity scores were the most improved in HBV. CONCLUSIONS: Prior to treatment, PRO scores were lower in patients with HCV in comparison to HBV. After successful treatment, both groups of patients experienced improvement in some PRO domains confirming the positive impact of treatment.

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.

The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma.

BACKGROUND: Targeting PLK1 has recently been proven as a viable therapeutic strategy against oesophageal squamous cell carcinom (ESCC). Therefore, this study aimed to explore whether the PLK1 inhibitor BI2536 is able to sensitize ESCC cells to cisplatin (DDP) and determine the underlying mechanisms. METHODS: Viability, clonogenicity, cell cycle distribution and apoptosis were assessed in ESCC cells treated with BI2536 or DDP alone or in combination. Checkpoint activation was examined by immunoblotting and immunohistochemistry. Xenograft model was used to assess the efficacy of the co-treatment. The expression level of GSDME in tissue samples were examined by immunohistochemistry. FINDINGS: We found that the combination of BI2536 and DDP was synergistic in ESCC cells, which induced pyroptosis in ESCC cells at low doses. Mechanistic studies revealed that BI2536 significantly induced DNA damage and impaired the DNA damage repair pathway in DDP-treated cells both in vitro and in vivo. Interestingly, we found that co-treatment with BI2536 and DDP induced pyroptosis in ESCC cells depending on the caspase-3/GSDME pathway. Importantly, our study found that GSDME was more highly expressed in tumour tissue than that in normal adjacent tissues, and could serve as a prognostic factor. INTERPRETATION: BI2536 sensitizes ESCC cells to DDP by inhibiting the DNA damage repair pathway and inducing pyroptosis, which provides new information for understanding pyroptosis. Our study also reveals that the PLK1 inhibitor BI2536 may be an attractive candidate for ESCC targeted therapy, especially when combined with DDP for treating the GSDME overexpression subtype. FUND: National 973 Program and National Natural Science Fundation of China.

Complex karyotype AML displays G2/M signature and hypersensitivity to PLK1 inhibition.

Patients diagnosed with acute myeloid leukemia with complex karyotype (CK AML) have an adverse prognosis using current therapies, especially when accompanied by TP53 alterations. We hereby report the RNA-sequencing analysis of the 68 CK AML samples included in the Leucegene 415 patient cohort. We confirm the frequent occurrence of TP53 alterations in this subgroup and further characterize the allele expression profile and transcript alterations of this gene. We also document that the RAS pathway (N/KRAS, NF1, PTPN11, BRAF) is frequently altered in this disease. Targeted chemical interrogation of genetically characterized primary CK AML samples identifies polo-like kinase 1 (PLK1) inhibitors as the most selective agents for this disease subgroup. TP53 status did not alter sensitivity to PLK1 inhibitors. Interestingly, CK AML specimens display a G2/M transcriptomic signature that includes higher expression levels of PLK1 and correlates with PLK1 inhibition sensitivity. Together, our results highlight vulnerability in CK AML. In line with these in vitro data, volasertib shows a strong anti-AML activity in xenotransplantation mouse models of human adverse AML. Considering that PLK1 inhibitors are currently being investigated clinically in AML and myelodysplastic syndromes, our results provide a new rationale for PLK1-directed therapy in patients with adverse cytogenetic AML.

Therapeutic potential of pteridine derivatives: A comprehensive review.

Pteridines are aromatic compounds formed by fused pyrazine and pyrimidine rings. Many living organisms synthesize pteridines, where they act as pigments, enzymatic cofactors, or immune system activation molecules. This variety of biological functions has motivated the synthesis of a huge number of pteridine derivatives with the aim of studying their therapeutic potential. This review gathers the state-of-the-art of pteridine derivatives, describing their biological activities and molecular targets. The antitumor activity of pteridine-based compounds is one of the most studied and advanced therapeutic potentials, for which several molecular targets have been identified. Nevertheless, pteridines are also considered as very promising therapeutics for the treatment of chronic inflammation-related diseases. On the other hand, many pteridine derivatives have been tested for antimicrobial activities but, although some of them resulted to be active in preliminary assays, a deeper research is needed in this area. Moreover, pteridines may be of use in the treatment of many other diseases, such as diabetes, osteoporosis, ischemia, or neurodegeneration, among others. Thus, the diversity of the biological activities shown by these compounds highlights the promising therapeutic use of pteridine derivatives. Indeed, methotrexate, pralatrexate, and triamterene are Food and Drug Administration approved pteridines, while many others are currently under study in clinical trials.

Dual TLR2 and TLR7 agonists as HIV latency-reversing agents.

The presence of a reservoir of latently infected cells in HIV-infected patients is a major barrier towards finding a cure. One active cure strategy is to find latency-reversing agents that induce viral reactivation, thus leading to immune cell recognition and elimination of latently infected cells, known as the shock-and-kill strategy. Therefore, the identification of molecules that reactivate latent HIV and increase immune activation has the potential to further these strategies into the clinic. Here, we characterized synthetic molecules composed of a TLR2 and a TLR7 agonist (dual TLR2/7 agonists) as latency-reversing agents and compared their activity with that of the TLR2 agonist Pam2CSK4 and the TLR7 agonist GS-9620. We found that these dual TLR2/7 agonists reactivate latency by 2 complementary mechanisms. The TLR2 component reactivates HIV by inducing NF-κB activation in memory CD4+ T cells, while the TLR7 component induces the secretion of TNF-α by monocytes and plasmacytoid dendritic cells, promoting viral reactivation in CD4+ T cells. Furthermore, the TLR2 component induces the secretion of IL-22, which promotes an antiviral state and blocks HIV infection in CD4+ T cells. Our study provides insight into the use of these agonists as a multipronged approach targeting eradication of latent HIV.