Lipid metabolism plays a pivotal role in maintaining systemic lipid homeostasis and preventing the development of atherosclerotic cardiovascular diseases. Within this network, apolipoprotein A-I (apoA-I) and lecithin-cholesterol acyltransferase (LCAT) are key players in reverse cholesterol transport (RCT). Dysfunctions in these processes, as highlighted by rare disorders such as LCAT deficiencies and Tangier disease, can significantly disrupt the delicate balance of lipid metabolism, ultimately impacting the development of cardiovascular diseases. Consequently, understanding the mechanistic principles that govern the functioning of apoA-I and LCAT has garnered substantial research interest over the years.
ApoA-I mimetic peptides, synthetic peptides that mimic the structure and function of apoA-I, have shown promising potential in promoting reverse cholesterol transport and reducing atherosclerosis progression in animal studies. These peptides interact with ATP-binding cassette transporters (ABCA1 and ABCG1), facilitating cholesterol efflux from peripheral tissues to high-density lipoproteins (HDL). Additionally, they can activate LCAT to varying degrees. However, the atom-scale mechanisms underlying these processes remain poorly understood
Positive allosteric modulators (PAMs) are compounds that enhance the catalytic activity of a target protein by binding to an allosteric site distinct from the active site. In the context of LCAT, PAMs have emerged as potential therapeutics to augment its enzymatic function. By binding to specific allosteric sites on LCAT, these modulators are believed to induce conformational changes that enhance the enzyme's affinity for lipoproteins, stimulate cholesterol esterification, and facilitate RCT. However, the exact atomistic interactions and conformational changes induced by PAMs to promote LCAT action remain unknown, and unraveling these details could provide valuable insights for the design of more effective therapeutics.
In the LLAB research group, our current focus is on understanding the mechanistic principles underlying the activation of LCAT by apoA-I mimetic peptides and positive allosteric modulators. Through uncovering the molecular interactions between these compounds and LCAT, we aim to develop novel or improved therapeutics that can restore impaired LCAT function, alleviate lipid accumulation, and attenuate the progression of atherosclerosis. By elucidating the underlying mechanisms, we aspire to contribute to the development of targeted and effective treatments for individuals affected by LCAT deficiencies and dyslipidemias.
Nanodiscs, which are discoidal lipid bilayers stabilized by membrane scaffold proteins, have emerged as invaluable tools for investigating the intricate structure and function of membrane-associated proteins. In the realm of lipid metabolism and cardiovascular diseases, understanding the organization and dynamic behavior of nanodiscs comprising apolipoprotein A-I (apoA-I) mimetic peptides and lipids holds profound significance. These synthetic peptides have been designed to replicate the structure and functionality of apoA-I, demonstrating immense potential in augmenting cholesterol efflux, fostering reverse cholesterol transport, and decreasing the progression of atherosclerosis. Despite these encouraging findings, the precise arrangement of apoA-I mimetic peptides along the rim of nanodiscs remains largely enigmatic, impeding our comprehensive understanding of the functional consequences of these peptides, particularly with regard to pharmacokinetics and enzymatic activities. Consequently, in the LLAB our research endeavors are centered around unraveling the structural properties of nanodiscs integrating apoA-I mimetic peptides and lipids. By acquiring mechanistic insights into these systems, we aim to optimize their therapeutic potential in the domain of dyslipidemias and targeted drug delivery applications, thus paving the way for innovative treatment strategies in the future.
The design of drug delivery vehicles utilizing nanodiscs has emerged as a promising approach. Nanodiscs, which are self-assembled structures composed of lipids and scaffold proteins, offer a versatile platform for the encapsulation and targeted delivery of therapeutic agents. By engineering the composition and properties of nanodiscs, such as their size, surface modification, and cargo-loading capacity, it becomes possible to tailor their behavior and optimize their performance as efficient carriers for drug molecules. This design strategy holds tremendous potential for improving drug stability, enhancing bioavailability, and achieving targeted delivery to specific tissues or cells. Consequently, one of the key research areas in the LLAB is the development of nanodisc-based therapeutics, leveraging a mechanistic approach, to address diverse disease conditions. By deeply understanding the underlying principles governing nanodisc behavior and interactions, we aim to design and engineer novel therapeutic platforms that can effectively target and treat various diseases.