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Discovery of potent small-molecule inhibitors of lipoprotein(a) formation

Journal Article · · Nature (London)
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  1. Lilly Research Laboratories, Alcobendas (Spain)
  2. Lilly Research Laboratories, Indianapolis, IN (United States)
  3. Lilly Research Laboratories, San Diego, CA (United States)
  4. Monash Univ., VIC (Australia)
+ Show Author Affiliations
Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a)). Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (KIV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) KIV7–8. We identify compounds that bind to apo(a) KIV7–8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329—which is already in phase 2 studies—as a potent and specific orally administered agent for reducing the levels of Lp(a).
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
2470151
Journal Information:
Nature (London), Journal Name: Nature (London) Journal Issue: 8013 Vol. 629; ISSN 0028-0836
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

References (30)

Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation journal September 2023
Association ofLPAVariants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies journal July 2018
Estimation of the Required Lipoprotein(a)-Lowering Therapeutic Effect Size for Reduction in Coronary Heart Disease Outcomes journal June 2019
Isothermal titration calorimetry (ITC): a standard operating procedure (SOP) journal March 2021
Prediction of cardiovascular risk by Lp(a) concentrations or genetic variants within the LPA gene region journal March 2019
Proposed mechanisms for binding of apo[a] kringle type 9 to apo B-100 in human lipoprotein[a] journal March 1993
Identification of the cysteine residue in apolipoprotein(a) that mediates extracellular coupling with apolipoprotein B-100. journal September 1993
Lipoprotein(a) beyond the kringle IV repeat polymorphism: The complexity of genetic variation in the LPA gene journal May 2022
The X-ray Crystal Structure of Full-Length Human Plasminogen journal March 2012
Comparative Analyses of the Lysine Binding Site Properties of Apolipoprotein(a) Kringle IV Types 7 and 10 journal December 2001
Identification of Sequences in Apolipoprotein(a) that Maintain Its Closed Conformation:  A Novel Role for Apo(a) Isoform Size in Determining the Efficiency of Covalent Lp(a) Formation journal July 2004
Sequences within Apolipoprotein(a) Kringle IV Types 6−8 Bind Directly to Low-Density Lipoprotein and Mediate Noncovalent Association of Apolipoprotein(a) with Apolipoprotein B-100 journal May 1998
Potent Fibrinolysis Inhibitor Discovered by Shape and Electrostatic Complementarity to the Drug Tranexamic Acid journal April 2013
Structural studies of plasmin inhibition journal March 2019
Lipoprotein(a) Reduction in Persons with Cardiovascular Disease journal January 2020
Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease journal November 2022
Cys4057 of apolipoprotein(a) is essential for lipoprotein(a) assembly. journal December 1993
Quantitative Evaluation of the Contribution of Weak Lysine-binding Sites Present within Apolipoprotein(a) Kringle IV Types 6–8 to Lipoprotein(a) Assembly journal January 2004
Identification and analyses of inhibitors targeting apolipoprotein(a) kringle domains KIV-7, KIV-10, and KV provide insight into kringle domain function journal April 2020
Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement journal August 2022
Single nucleotide polymorphisms in exons of the apo(a) kringles IV types 6 to 10 domain affect Lp(a) plasma concentrations and have different patterns in Africans and Caucasians journal April 2001
Molecular basis of congenital lp(a) deficiency: a frequent apo(a) 'null' mutation in caucasians journal October 1999
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
The CCP4 suite: integrative software for macromolecular crystallography journal May 2023
Inhibitors for the In Vitro Assembly of Lp(a) journal October 1995
Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association journal January 2022
Lipoprotein(a)-Lowering by 50 mg/dL (105 nmol/L) May Be Needed to Reduce Cardiovascular Disease 20% in Secondary Prevention journal January 2020
Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease journal January 2021
Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program journal March 2023
Structure, function, and genetics of lipoprotein (a) journal August 2016

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
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x-ray crystallography