Abstract
The abundant blood protein α1-proteinase inhibitor (α1PI, Αlpha-1, α1-antitrypsin, SerpinA1) is known to bind to the active site of granule-associated human leukocyte elastase (HLE-G). Less well known is that binding of α1PI to cell surface HLE (HLE-CS) induces lymphocyte locomotion mediated by members of the low density lipoprotein receptor family (LDL-RFMs) thereby facilitating low density lipoprotein (LDL) clearance. LDL and α1PI were previously shown to be in negative feedback regulation during transport and clearance of lipoproteins. Further examination herein of the influence of α1PI in lipoprotein regulation using data from a small randomized, double-blind clinical trial shows that treatment of HIV-1-infected individuals with α1PI plasma products lowered apolipoprotein and lipoprotein levels including LDL. Although promising, plasma-purified α1PI is limited in quantity and not a feasible treatment for the vast number of people who need treatment for lowering LDL levels. We sought to develop orally available small molecules to act as surrogates for α1PI. Small molecule β-lactams are highly characterized for their binding to the active site of HLE-G including crystallographic studies at 1.84 Å. Using high throughput screening (HLE-G inhibition, HLE-CS-induced cellular locomotion), we show here that a panel of β-lactams, including the LDL-lowering drug ezetimibe, have the capacity to act as surrogates for α1PI by binding to HLE-G and HLE-CS. Because β-lactams are antibiotics that also have the capacity to promote evolution of antibiotic resistant bacteria, we modified the β-lactam Alphataxin to prevent antibiotic activity. We demonstrate using the diet-induced obesity (DIO) mouse model that Alphataxin, a penam, is as effective in lowering LDL levels as FDA-approved ezetimibe, a monobactam. Non-antibiotic β-lactams provide a promising new therapeutic class of small molecules for lowering LDL levels.
Highlights
The abundant blood protein α1-proteinase inhibitor (α1PI, Alpha-1, α1-antitrypsin, SerpinA1) binds to the active site of granule-associated human leukocyte elastase (HLE-G) forming a covalent-like complex that inactivates both HLE-G and α1PI (Beatty et al, 1980; Herve and Ghelis, 1991)
Changes in lipoprotein and apolipoprotein levels following Prolastin-C treatment in HIV-1-infected individuals suggest that α1PI is not functionally related to apoB100 levels, but is directly or indirectly related to apolipoprotein B-48 (apoB48), apolipoprotein E (apoE), apolipoprotein A1 (apoA1), high density lipoprotein (HDL), low density lipoprotein (LDL), and triglyceride levels
ApoA1 is found in chylomicrons and HDL; apoE is found in chylomicron remnants and HDL (Feingold, 2021)
Summary
The abundant blood protein α1-proteinase inhibitor (α1PI, Alpha-1, α1-antitrypsin, SerpinA1) binds to the active site of granule-associated human leukocyte elastase (HLE-G) forming a covalent-like complex that inactivates both HLE-G and α1PI (Beatty et al, 1980; Herve and Ghelis, 1991). We sought to develop an orally available small molecule to act as a surrogate for α1PI to complex with HLE-CS thereby inducing cellular locomotion and increasing transport and clearance of LDL via LDL-RFMs. Small molecule β-lactams are highly characterized including their binding to the active site of HLE-G in crystallographic studies at 1.84 Å (Navia et al, 1987; Bonney et al, 1989; Doherty et al, 1993). A form of cefuroxime was examined in uninfected beagles and showed an increase in reticulocytes in treated animals as compared with untreated animals and a decrease in leukocytes during treatment in female animals; cholesterol levels were consistently lower in treated animals in comparison with untreated animals even though triglyceride levels were significantly greater in treated as compared with untreated animals suggesting the effect was associated with liver production of lipoproteins as opposed to fat absorption by enterocytes (Spurling et al, 1986). We show in preclinical in vivo studies using the Jackson Laboratory diet-induced obesity mouse model of human metabolic syndrome and diabetes (DIO) that Alphataxin, a penam, effectively lowered LDL levels equivalently to ezetimibe, a monobactam
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