Biology subjects

Chandramohanadas, R.

Publications and source records attributed to Chandramohanadas, R..

3 recordsLinked to original sources

bioRxiv2024

Functional Phenotyping of MMV Pandemic Response Box Identifies Stage-specific inhibitors Against Blood stage Plasmodium

Wide-spread resistance to clinically used antimalarials necessitates the prioritization of novel scaffolds with alternate mechanisms, as possible partner drugs to artemisinin. We utilized the Pandemic Response Box chemical library of the Medicines for Malaria Venture launched in 2019 to identify inhibitors with stage-specific potency and phenotypic signatures against P. falciparum towards exploring the possibility of drug repurposing. From this screening, we initially identified 60 molecules active against both drug sensitive (3D7) and chloroquine resistant (Dd2) strains of P. falciparum. Further, 28 active compounds active below 3{micro}M were prioritized several of which specifically impaired stage-transitions of ring (MMV001014), trophozoite (MMV1593540 and MMV1634402) and schizonts (MMV1580844, MMV1580496, MMV1580173 and MMV1580483) confirmed through microscopic phenotypes and flow cytometry. The ring stage inhibitor, MMV001014, was irreversible, led to no recrudescence and showed antagonistic effects with artemisinin indicative of overlapping mechanism. Both the trophozoite inhibitors exhibited nanomolar IC50 with non-compromised digestive vacuole. MMV1593540 was partially additive with artemisinin while antagonistic with chloroquine. Two among the schizont stage inhibitors (MMV1580844 and MMV1580496) appeared to operate through a mechanism driven by the generation of reactive oxygen species and all of them with molecule-specific effect on infected red blood cell (RBC) membrane integrity confirmed through confocal microscopy. Taken together, these results highlight interesting starting points derived from MMVs Pandemic Response Box for repurposing to combat Malaria that continues to morbidly affect the developing world. ImportanceMalaria caused by infectious parasites belonging to the Plasmodium family continues to morbidly affect the marginalized populations. The situation is further complicated by lack of mass vaccination, drug resistance, and emergence of new parasitic forms. To alleviate the threat of drug resistance, it is important to identify new drugs acting through mechanisms distinct from the existing ones such as artemisinin. This work describes the screening of a chemical compound library against blood stage development of malaria parasites and prioritization of molecules that can inhibit parasite development in a stage-specific manner. Several of these compounds demonstrate nanomolar potency against sensitive and resistant forms of the parasites acting through distinctive mechanisms. Exploring the modes of action of these molecules will facilitate their optimization and possible clinical applications against the deadly diseases, Malaria.

microbiology↗

bioRxiv2023

Structure-based virtual screening and Molecular Dynamic Simulations identified FDA-approved molecules as potential inhibitors against the surface proteins of H1N1

H1N1, a subtype of influenza A virus, remains a global concern due to its ability to cause highly contagious, and fatal infections of the respiratory tract that can lead to seasonal pandemics. Factors such as genetic reassortment and antigenic shift due to the segmented nature of its RNA genome, lead to its rapid evolution that impacts drug and vaccine interactions. Thus, there is growing interest in identifying small-molecules against H1N1 to address the challenges posed by its ever-changing nature and enhance ability to combat the virus. By targeting the surface proteins crucial in the viral life cycle and interactions with host cells, we conducted structure-based virtual screening of 2,471 FDA-approved small molecules against H1N1s hemagglutinin (HA) and neuraminidase (NA) using molecular docking, and molecular dynamic simulations. A binding pocket for HA was identified at the interface of the three protomers, close to the fusion peptide, while in the case of NA the co-crystal ligand binding site was targeted. We identified 5 molecules, namely Econazole, Butoconazole, Miconazole, Isoconazole, and Tioconazole with higher binding affinity to HA and 4 molecules, namely Acarbose, Rutin, Paromomycin, and Idarubicin showing superior binding affinity to NA. Further molecular dynamic simulation of these molecules bound with HA and NA reaffirm the stability of the complexes. These molecules are known to have antifungal and antiviral properties. Thus, this study elucidates the importance of targeting HA and NA and paves the way for repurposing existing antivirals, antibacterials, and antifungals as inhibitors of the H1N1 viral entry into host cells.

bioinformatics↗

bioRxiv2019

Reticulocyte Infection Leads to Altered Behaviour, Drug Sensitivity and Host Cell Remodelling by Plasmodium falciparum.

Plasmodia are host-specific, both at the organism and cellular levels. During asexual development, Plasmodium spp. infect cells of erythroid lineage, with an overall propensity towards reticulocytes. This applies to even Plasmodium (P.) falciparum, the most common causative agent of human malaria, implications of which remain unexplored. Herein, for the first time, we characterize the developmental stages and features of P. falciparum cultured in vitro in young reticulocytes (CD71+) in comparison to standard normocyte (CD71-) cultures. We demonstrate that there are notable differences in the patterns of invasion, development and sensitivity to potent antimalarials (such as artemisinin and dihydroartemisinin) for parasites residing in CD71+ reticulocytes. Through a transcriptomic approach, we report that P. falciparum parasites are able to sense the host cell environment, and calibrate their metabolic and host cell remodelling pathways through differential gene expression. These results form an exciting avenue on which hitherto unexplored interactions between Plasmodium spp and different stages of host red blood cells could be investigated in the broader contexts of drug resistance, host tropism and zoonosis. Author SummaryParasites causing malaria infect red blood cells for development and proliferation during asexual development. This asexual erythrocytic stage determines higher parasite densities and eventual disease manifestation. Although the most virulent species of Plasmodium infecting humans known as Plasmodium falciparum is able to infect red blood cells of all ages, these parasites show a preference for younger blood cells. Of note, the biochemical and biophysical properties of young and adult red blood cells vary significantly. Herein, we undertook a comparative profiling of invasion process, parasite development and drug response of Plasmoddium falciparum in two host cells: young red blood cells (reticulocytes) and mature red blood cells (normocytes). We demonstrate that P. falciparum infects human reticulocytes with higher affinity and demonstrate differential sensitivity to drugs such as artemisinin while they reside within reticulocytes. Furthermore, we show that P. falciparum is able to detect differences in host environment and adapt to it by changing the expression of genes required for host cell remodelling.

microbiology↗