The functional versatility of ARSs warrants multiple therapeutic routes.
ARS Targeting Strategy
- Route 1 seeks for unique pharmacological efficacy by targeting the catalytic site.
- Route 2 explores therapeutic opportunity from extracellular ARSs.
- Route 3 intervenes the disease-associated protein-protein interactions between human ARSs and their interactors.
With the deep-understanding of ARS biology, AIBI is developing the paradigm-shifting novel therapeutics to fill up the clinical unmet needs in difficult diseases with no cure.
Over the past few years, there has been a drastic increase in data digitalization in the pharmaceutical sector. However, this digitalization comes with the challenge of acquiring, scrutinizing, and applying that knowledge to solve complex clinical problems. This motivates the use of AI, because it can handle large volumes of data with enhanced automation. AI is a technology-based system involving various advanced tools and networks that can mimic human intelligence. At the same time, it does not threaten to replace human physical presence completely. AI utilizes systems and software that can interpret and learn from the input data to make independent decisions for accomplishing specific objectives.
Chemical design of targeting ARS catalytic region
PARS1 inhibitors
In collaboration with Daewoong Pharma
PARS1 is an enzyme that conjugates amino acid proline to its tRNA to generate prolyl-tRNA to be used in protein synthesis. Since proline is one of major components of collagen, suppression of PARS1 would down-regulate collagen synthesis, which could be beneficial in fibrosis. Thus, a selective inhibitor of PARS1 could serve as a potent anti-fibrotic agent.
MARS1 and CDK4
In collaboration with Gangnam severance hospital
MARS1 specifically stabilizes CDK4 by enhancing the formation of the complex between CDK4 and a chaperone protein. Knockdown of MARS1 reduced the CDK4 level, resulting in G0/G1 cell cycle arrest. The effects of MARS1 on CDK4 stability were more prominent in the tumor suppressor p16INK4a-negative cancer cells.
Design of specific ARS targeting antibodies (In collaboration with Zymedi)
Lysyl-tRNA syntehtase 1 (KARS1)
KARS1 is one of ARSs, specifically connecting lysine to tRNALys for protein synthesis. Like other ARSs, it mainly exists in cytosol in normal situation. However, a portion of KARS1 is translocated to the cell membrane of monocyte to trigger migration. Among immune cells, this unique activity is particularly prominent in monocytes and macrophages. Fibrosis commonly involves chronic inflammation resulting from the infiltration of monocyte and macrophages. Therefore, therapeutics to control monocyte and macrophages migration can be applied to diverse fibrotic diseases.
KARS1 antibody
KARS1 can be located on the plasma membrane of monocytes and macrophages and facilitates their migration to damaged tissues. Our human antibody binds to a region of KARS1 that is exposed on the cell surface and induces rapid endocytosis of KARS1. Therefore, removes membrane KARS1, inhibiting KARS1-mediated movement of monocytes and macrophages.
Development of ARS-derived biologic
The ARS have the domain which can control diverse cellular process, such as immunity, angiogenesis, tissue regeneration and metabolism. The inherent domain in ARS could be exploited for the development of novel therapies.
CARS1
In collaboration with KRIBB
A unique domain (UNE-C1) inserted into the catalytic region of CARS1 was determined as the endogenous TLR2/6 activating domain. Thus, the UNE-C1 domain can be developed as an effective immunoadjuvant.
EPRS1
In collaboration with KRIBB
Viral infection specifically induces phosphorylation of EPRS1 at Ser990, which subsequently leads to the dissociation of EPRS1 from the MSC. The dissociated EPRS1 interacts with PCBP2 and blocks PCBP2-mediated MAVS ubiquitination, which in turn inhibits viral replication.
GARS1
GARS1 is specifically secreted from tumor-associated macrophages and induces tumor cell death through interaction with K-cadherin, resulting in deactivation of the ERK pathway.
AIMP1
ARS-interacting multi-functional protein 1 (AIMP1) is secreted from macrophages in the damaged tissue. Its binding to fibroblasts stimulates ERK signal activation, fibroblast proliferation and collagen production that facilitates wound healing.
Chemical design of ARS-mediated protein-protein interactions
KARS1 and 67LR
In collaboration with Zymedi
KARS1 relocates to the plasma membrane after a laminin signal and stabilizes a 67LR that is implicated in cancer metastasis. Specific modulation of a cancer-related KARS1-67LR interaction can offer a way to control metastasis.
LARS1 and RagD
In collaboration with
Yonsei University College of Pharmacy
LARS1 is known to function as a leucine sensor for activating the mTORC1 pathway. Chemicals interfering with the interaction between LARS1 and RagD can be applied to mTORC1 dysregulated diseases such as various cancers, epilepsy and Alzheimer’s disease.
AIMP2-DX2 and KRAS
In collaboration with Zymedi
차후에 보완 예정.
AIMP2-DX2 stabilizes KRAS, a putative oncogenic factor in cancer. Chemical compounds interfering with the interaction between AIMP2-DX2 and KRAS can offer a way to suppress KRAS-driven tumorigenesis.