Biology subjects

Babu, S.

Publications and source records attributed to Babu, S..

22 records · Page 2Linked to original sources

bioRxiv2020

A Cyclic Phosphoramidate Prodrug of 2-deoxy-2-fluoro-2-C-methylguanosine for the Treatment of Dengue Infection

Monophosphate prodrug analogs of 2-deoxy-2-fluoro-2-C-methylguanosine have been reported as potent inhibitors of hepatitis C virus (HCV) RNA-dependent RNA polymerase. These prodrugs also display potent anti-dengue activities in cellular assays although their prodrug moieties were designed to produce high levels of triphosphate in the liver. Since peripheral blood mononuclear cells (PBMCs) are one of the major targets of dengue virus, different prodrug moieties were designed to effectively deliver 2-deoxy-2-fluoro-2-C-methylguanosine monophosphate prodrugs and their corresponding triphosphates into PBMCs after oral administration. We identified a cyclic phosphoramidate prodrug 17 demonstrating a well-balanced anti-dengue cellular activity and in vitro stability profiles. In dogs, oral administration of 17 resulted in high PBMC triphosphate level, exceeding TP50 (the intracellular triphosphate concentration at which 50% of virus replication is inhibited) at 10 mg/kg. Compound 17 demonstrated 1.6- and 2.2 log viremia reduction in the dengue mouse model at 100 and 300 mg/kg twice daily, respectively. At 100 mg/kg twice daily, the terminal triphosphate concentration in PBMCs reached above TP50, defining for the first time the minimum efficacious dose for a nucleos(t)ide prodrug. In the two-week dog toxicity studies at 30 to 300 mg/kg/day, no observed adverse effect level (NOAEL) could not be achieved due to pulmonary inflammation and hemorrhage. The preclinical safety results suspended further development of 17. Nevertheless, present work has proven the concept that an efficacious monophosphate nucleoside prodrug could be developed for the potential treatment of dengue infection.

microbiology↗

bioRxiv2020

Aging increases the systemic molecular degree of inflammatory perturbation in patients with tuberculosis

Tuberculosis (TB) in a chronic infection that can affect individuals of all ages. The description of determinants of immunopathogenesis in TB is a field of tremendous interest due to the perspective of finding a reliable host-directed therapy to reduce disease burden. The association between specific biomarker profiles related to inflammation and the diverse clinical disease presentations in TB has been extensively studied in adults. However, relatively scarce data on profiling the inflammatory responses in pediatric TB are available. Here, we employed the molecular degree of perturbation (MDP) score adapted to plasma biomarkers in two distinct databanks from studies that examined either adults or children presenting with pulmonary or extrapulmonary disease. We used multidimensional statistical analyses to characterize the impact of age on the overall changes in the systemic inflammation profiles in subpopulation of TB patients. Our findings indicated that TB results in significant increases in MDP values, with the highest values being detected in adult patients. Furthermore, there were unique differences in the biomarker perturbation patterns and the overall degree of inflammation according to disease site and age. Importantly, the molecular degree of perturbation was not influenced by sex. Our results revealed that aging is an important determinant of the differences in quality and magnitude of systemic inflammatory perturbation in distinct clinical forms of TB.

immunology↗

bioRxiv2019

An unbiased high-throughput drug screen reveals a potential therapeutic vulnerability in the most lethal molecular subtype of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related deaths in the United States by 2020, due in part to innate resistance to widely used chemotherapeutic agents and limited knowledge about key molecular factors that drive tumor aggression. We previously reported a novel negative prognostic biomarker, keratin 17 (K17), whose overexpression in cancer results in shortened patient survival. In this study, we aimed to determine the predictive value of K17 and explore the therapeutic vulnerability in K17-expressing PDAC, using an unbiased high-throughput drug screen. Patient-derived data analysis showed that K17 expression correlates with resistance to Gemcitabine (Gem). In multiple in vitro models of PDAC, spanning human and murine PDAC cells, we determined that the expression of K17 results in a more than two-fold increase in resistance to Gem and 5-fluorouracil, key components of current standard-of-care chemotherapeutic regimens. Furthermore, through an unbiased drug screen, we discovered that Podophyllotoxin (PPT), a microtubule inhibitor, showed at least two-fold higher sensitivity in K17-expressing compared to K17-negative PDAC cells. In the clinic, another microtubule inhibitor, Paclitaxel (PTX), is used in combination with Gem as a first line chemotherapeutic regimen for pancreatic, breast, lung, and ovarian cancer. Surprisingly, we found that when combined with Gem, PPT but not PTX, was synergistic in inhibiting the viability of K17-expressing PDAC cells. This provides evidence that PPT or its derivatives could potentially be combined with Gem to enhance treatment efficacy for the approximately 50% of PDACs that express high levels of K17. In summary, we reported that K17 is a novel target for developing a biomarker-based personalized treatment for PDAC.

cancer biology↗

bioRxiv2019

Staphylococcus pasteuri isolates (Spvs) from human atherosclerotic plaques mediate virulence, intracellular resistance and transendothelial invasion of macrophages: A mechanistic paradigm for microbial pathogenicity in atherosclerosis

Atherosclerotic cardiovascular disease, a chronic inflammatory condition of multifactorial etiology, is the leading cause of death worldwide. The concept of bacterial persistence has been proposed as one of several contributing factors to this disease. We hypothesized that the infectious agent(s) found at the site of the atheroma may be dormant but perpetuate virulence in response to host defense and other physiological triggers. In this study, we sought to identify the source of persistent infection in human atherosclerotic plaque and define how pathogen virulence and host defenses mediate plaque vulnerability. Whole genome sequencing (WGS) was used to identify bacteria from pure cultures obtained from atherosclerotic tissues of living subjects diagnosed with more than 70% occlusion of the carotid artery undergoing carotid endarterectomy (CE). WGS identified the predominant species as S. pasteuri (Spv) in all CE isolates grown in pure culture except one isolate which was identified as B. licheniformis. All S. pasteuri isolates (Spvs) were found to contain genes for widespread virulence, invasion, and intracellular resistance. As macrophages (M{varphi}s) play a decisive role at all stages of this disease we treated mouse M{varphi}s (RAW 264.7) with Spvs. While all Spvs tested demonstrated their ability to survive phagocytosis, the highly virulent Spvs also activated M{varphi}s and induced trans-endothelial cell migration of these cells which was mediated via the CC chemokine CCL1 and its receptor CCR8. In conclusion, we show that Spvs are found in CE plaques, have the capacity to survive phagocytosis and induce the transmigration of M{varphi}s across an endothelial barrier in a CCL1-CCR8 dependent process. These findings highlight the significance of carotid vessels as a reservoir for S. pasteuri, a pathogen found in products used routinely in human consumption; this may explain how microbial pathogenicity modulates plaque vulnerability in atherosclerosis.

pathology↗