A novel isothiocyanate derivative inhibits HIV-1 gene expression and replication by modulating the nuclear matrix associated protein SMAR1

Trivedi, Jay; Alam, Aftab; Joshi, Shruti; Kumar, Togapur Pavan; Chippala, Venkatraju; Mainkar, Prathama S.; Chandrasekhar, S.; Chattopadhyay, Samit; Mitra, Debashis

doi:10.1016/j.antiviral.2019.104648

Cited by 7 publications

(3 citation statements)

References 59 publications

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“…Determination of infectivity of prepared virus stocks-TZMbl cells were seeded at the density of 0.125 3 10 6 cells/well of a 24-well plate containing 500 ml of DMEM (Gibco) supplemented with 10% FBS (Gibco) and 1% penicillin/streptomycin (Gibco). 12 h postseeding, the medium from each well was replaced with fresh complete medium, and the cells were infected with different concentrations of HIV-1 JRFL and HIV-1 YU2 as described previously (56). 48 h postinfection, medium was removed, and infected cells were fixed with 0.1% formaldehyde.…”

Section: Characterization Of Anti-hiv Activity Of Horcolinmentioning

confidence: 99%

The barley lectin, horcolin, binds high-mannose glycans in a multivalent fashion, enabling high-affinity, specific inhibition of cellular HIV infection

Jayaprakash

Singh

Vivek

et al. 2020

Journal of Biological Chemistry

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N-linked glycans are critical to the infection cycle of HIV, and most neutralizing antibodies target the high-mannose glycans found on the surface envelope glycoprotein-120 (gp-120). Carbohydrate-binding proteins, particularly mannose-binding lectins have also been shown to bind these glycans. Despite their therapeutic potency their ability to cause lymphocyte proliferation limits their application. In this study we report one such lectin named Horcolin (Hordeum vulgare lectin), seen to lack mitogenicity owing to the divergence in the residues at its carbohydrate-binding sites which makes it a promising candidate for exploration as an anti-HIV agent. Extensive ITC experiments reveal that the lectin was sensitive to the length and branching of mannooligosaccharides and thereby the total valency. Modeling and simulation studies demonstrate two distinct modes of binding, a monovalent binding to shorter saccharides and a bivalent mode for higher glycans, involving simultaneous interactions of multiple glycan arms with the primary carbohydrate binding sites. This multivalent mode of binding was further strengthened by interactions of core mannosyl residues with secondary conserved site on the protein, leading to an exponential increase in affinity. Finally, we confirmed the interaction of Horcolin with recombinant gp120 and gp140 with high affinity, and inhibition of HIV infection at nanomolar concentrations without mitogenicity.

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Section: Characterization Of Anti-hiv Activity Of Horcolinmentioning

confidence: 99%

The barley lectin, horcolin, binds high-mannose glycans in a multivalent fashion, enabling high-affinity, specific inhibition of cellular HIV infection

Jayaprakash

Singh

Vivek

et al. 2020

Journal of Biological Chemistry

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“…Furthermore, microbial peptides that promote SMAR1 stabilization have been correlated with inhibition of Wnt/β-catenin activities in CRC 24 . A study involving stabilization of SMAR1 expression by treatment with isothiocyanate derivative has been co-related with anti-HIV activity 44 . Our ndings reveal that SMAR1 knockdown promotes the Warburg effect and tumorigenic potential of breast cancer cells by modulating PKM isoform expression indicating an important regulatory role of tumor suppressor protein in cellular homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Tumor Suppressor SMAR1 Regulates PKM Alternative Splicing by HDAC6 Mediated Deacetylation of PTBP1

Choksi

Parulekar

Pant

et al. 2021

Preprint

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Background:Highly proliferating cancer cells exhibit the Warburg effect by regulation of PKM alternative splicing and promoting the expression of PKM2. Majority of the alternative splicing events are known to occur in the nuclear matrix where various MARBPs actively participate in the alternative splicing events. SMAR1, being a MARBP and an important tumor suppressor, is known to regulate the splicing of various cancer-associated genes. This study focuses on the regulation of PKM alternative splicing and inhibition of the Warburg effect by SMAR1.Methods:Immunohistochemistry was performed in breast cancer patient samples to establish the correlation between SMAR1 and PKM isoform expression. Further, expression of PKM isoforms upon modulation in SMAR1 expression in breast cancer cell lines was quantified by qRT-PCR and western blot. The acetylation status of PTBP1 was estimated by immunoprecipitation along with its enrichment on PKM pre-mRNA by CLIP in SMAR1 knockdown conditions. The role of SMAR1 in tumor metabolism and tumorigenesis was explored by in vitro enzymatic assays and functional assays upon SMAR1 knockdown. Besides, in vivo tumor formation by injecting adeno-SMAR1 transduced MDA-MB-231 cells in NOD/SCID mice was performed. Results:The expression profile of SMAR1 and PKM isoforms in breast cancer patients revealed that SMAR1 has an inverse correlation with PKM2 and a positive correlation with PKM1. Further quantitative PKM isoform expression upon modulation in SMAR1 expression also reflects that SMAR1 promotes the expression of PKM1 over tumorigenic isoform PKM2. SMAR1 deacetylates PTBP1 via recruitment of HDAC6 resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. SMAR1 inhibits the Warburg effect, tumorigenic potential of cancer cells and in vivo tumor generation in PKM2 dependent manner.Conclusions:SMAR1 regulates PKM alternative splicing by causing HDAC6 dependent deacetylation of PTBP1, resulting in reduced enrichment of PTBP1 on PKM pre-mRNA. Additionally, SMAR1 suppresses glucose utilization and lactate production via repression of PKM2 expression. This suggests that tumor suppressor SMAR1 inhibits tumor cell metabolism and tumorigenic properties of cancer cells via regulation of PKM alternative splicing.

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“…Interestingly, >98% of HIV sequences contain an S/MAR element. And studies from our lab have shown that SMAR1 binds to the HIV long terminal repeat (LTR) S/MAR and reinforces transcriptional repression (Sreenath et al, 2010;Trivedi et al, 2020). It would be interesting to see if this involves any PTM and if targeting of that PTM may be used to break the latency.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Chemical Decorations of “MARs” Residents in Orchestrating Eukaryotic Gene Regulation

Roychowdhury

Chattopadhyay

2020

Front. Cell Dev. Biol.

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Genome organization plays a crucial role in gene regulation, orchestrating multiple cellular functions. A meshwork of proteins constituting a three-dimensional (3D) matrix helps in maintaining the genomic architecture. Sequences of DNA that are involved in tethering the chromatin to the matrix are called scaffold/matrix attachment regions (S/MARs), and the proteins that bind to these sequences and mediate tethering are termed S/MAR-binding proteins (S/MARBPs). The regulation of S/MARBPs is important for cellular functions and is altered under different conditions. Limited information is available presently to understand the structure–function relationship conclusively. Although all S/MARBPs bind to DNA, their context- and tissue-specific regulatory roles cannot be justified solely based on the available information on their structures. Conformational changes in a protein lead to changes in protein–protein interactions (PPIs) that essentially would regulate functional outcomes. A well-studied form of protein regulation is post-translational modification (PTM). It involves disulfide bond formation, cleavage of precursor proteins, and addition or removal of low-molecular-weight groups, leading to modifications like phosphorylation, methylation, SUMOylation, acetylation, PARylation, and ubiquitination. These chemical modifications lead to varied functional outcomes by mechanisms like modifying DNA–protein interactions and PPIs, altering protein function, stability, and crosstalk with other PTMs regulating subcellular localizations. S/MARBPs are reported to be regulated by PTMs, thereby contributing to gene regulation. In this review, we discuss the current understanding, scope, disease implications, and future perspectives of the diverse PTMs regulating functions of S/MARBPs.

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A novel isothiocyanate derivative inhibits HIV-1 gene expression and replication by modulating the nuclear matrix associated protein SMAR1

Cited by 7 publications

References 59 publications

The barley lectin, horcolin, binds high-mannose glycans in a multivalent fashion, enabling high-affinity, specific inhibition of cellular HIV infection

The barley lectin, horcolin, binds high-mannose glycans in a multivalent fashion, enabling high-affinity, specific inhibition of cellular HIV infection

Tumor Suppressor SMAR1 Regulates PKM Alternative Splicing by HDAC6 Mediated Deacetylation of PTBP1

Chemical Decorations of “MARs” Residents in Orchestrating Eukaryotic Gene Regulation

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