Biology subjects

Belkaya, S.

Publications and source records attributed to Belkaya, S..

4 recordsLinked to original sources

bioRxiv2026

Synthetic Hybrid Receptors for Safer and Programmable T Cell Therapy

Engineered T cell therapies have achieved significant clinical success in hematological malignancies but remain largely ineffective in solid tumors. Overcoming this limitation requires strategies that enhance T cell function while avoiding systemic immune toxicities and pathological T cell states. Existing approaches typically rely on constitutive gene overexpression or suppression to augment potency or remodel the tumor microenvironment, but these strategies frequently lead to dysregulated immune activation and dose-limiting toxicity. Here, we present Hybrid Receptors (Hybrid-Rs), a modular receptor platform that integrates features of chimeric antigen receptors (CARs) and SyNthetic Intramembrane Proteolysis Receptors (SNIPRs) to couple antigen-dependent T cell activation with programmable gene regulation. Hybrid-Rs enable precise, context-dependent control of T cell potency, differentiation states, and conditional expression of secreted immunotherapeutic payloads with otherwise prohibitive toxicity. Hybrid-Rs are readily humanized and compatible with precision genome editing in primary human T cells, providing a direct and practical path to clinical translation.

bioengineering↗

bioRxiv2024

Computational Modeling of the Anti-Inflammatory Complexes of IL37

Interleukin (IL) 37 is an anti-inflammatory cytokine belonging to the IL1 protein family. Owing to its pivotal role in modulating immune responses, particularly through interfering with the IL18 signaling, elucidating the IL37 complex structures holds substantial therapeutic promise for various autoimmune disorders and cancers. Although the structural homology between IL37 and IL18 suggests a common binding mechanism with the primary members of IL18 signaling, the structures of IL37 complexes have not been experimentally resolvet yet. This computational study aims to address this gap through molecular modeling and classical molecular dynamics simulations, revealing the structural underpinnings of its modulatory effects on the IL18 signaling pathway. All IL37 protein-protein complexes, including both receptordependent and receptor-independent pairs, were modeled using a range of methods from homology modeling to AlphaFold2 multimer predictions. The models that successfully captured experimental features were subjected to molecular dynamics simulations. As positive controls, binary and ternary PDB complexes of IL18 were also included. The comparative look on the IL37 and IL18 complexes revealed a highly dynamic nature for the IL37 complexes. Repeated simulations of IL37-IL18R showed altered receptor conformations capable of accommodating IL37 in its dimeric form without clashes, providing a structural basis for the failure of IL18R{beta} to be recruited to the IL37-IL18R complex. Simulations of receptor complexes involving various mature forms of IL37 revealed that the N-terminal loop of IL37 is pivotal in modulating receptor dynamics. Additionally, the glycosyl chains on the primary receptor residue N297 act as a steric block against the IL37s N-terminal loop. The interactions between IL37 and IL18BP were also investigated, and our dynamical models indicated that a homologous binding mode was unlikely, suggesting an alternative mechanism by which IL37 functions as an anti-inflammatory cytokine upon binding to IL18BP. Altogether this study accesses to the structure and dynamics of IL37 complexes, offering molecular insights into IL37s inhibitory function within the IL18 signaling pathway and informing future experimental research. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/613817v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@ab5419org.highwire.dtl.DTLVardef@1e7126org.highwire.dtl.DTLVardef@968436org.highwire.dtl.DTLVardef@1c1fec2_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

immunology↗

bioRxiv2024

Rational Design of Monomeric IL37 Variants Guided by Stability and Dynamical Analyses of IL37 Dimers

IL37 plays important roles in the regulation of innate immunity and its oligomeric status is critical to these roles. In its monomeric state, IL37 can effectively inhibit the inflammatory response triggered by IL18 through binding to the IL18 receptor , a capability lost in its dimeric form. This paradigm underscores the pivotal role of IL37s dimer structure in the design of novel anti-inflammatory therapeutics. Hitherto, two IL37 dimer structures were deposited in PDB, reflecting the potential use of their binding interface in the design of IL37 variants with altered dimerization tendencies. Inspection of these static structures suggested a substantial difference in their dimer interfaces. Prompted by this discrepancy, we analyzed the PDB structures of IL37 dimer (PDB: 6ncu and 5hn1) along with a predicted structure by AF2-multimer by molecular dynamics (MD) simulations to unravel whether and how IL37 can form homodimers through distinct interfaces. Results showed that the 5hn1 and AF2 dimers, which shared the same interface, stably maintained their initial conformations throughout the simulations whilst the recent IL37 dimer (PDB ID: 6ncu) with a different interface, did not. These findings underscored that the recent IL37 dimer (6ncu) structure is likely to contain an error, probably in its biological assembly record, otherwise it was not a stable assembly in silico. Next, focusing on the stable dimer structure of 5hn1, we have identified five critical positions of V71/Y85/I86/E89/S114 that would altogether reduce dimer stability without affecting the monomer fold. Two quintet mutations were tested similarly by MD simulations and both mutations showed either partial or complete dissociation of the dimeric form. Overall, this work contributes to the development of IL37-based therapeutics by accurately representing the dimer interface in the PDB structures and identifying five potential substitutions to effectively inhibit the inflammatory response triggered by IL18.

immunology↗

bioRxiv2020

Human hepatocyte PNPLA3 148M exacerbates rapid non-alcoholic steatohepatitis development in chimeric mice

Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of chimeric mice respond to a hypercaloric Western-style diet. As early as 4 weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatohepatitis selectively in the human graft, followed by pericellular fibrosis after 8 weeks of hypercaloric feeding. The PNPLA3 148M variant, either from a homozygous 148M human donor or overexpressed in a homozygous 148I donor background, caused widespread microvesicular steatosis and even more severe steatohepatitis. We conclude that PNPLA3 148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variants associated with advanced fatty liver diseases.

pathology↗