PCSK9 as a Target for Development of a New Generation of Hypolipidemic Drugs
Nikolay Kuzmich,
Elena Andresyuk,
Yuri Porozov,
Vadim Tarasov,
Mikhail Samsonov,
Nina Preferanskaya,
Valery Veselov,
Renad Alyautdin
Affiliations
Nikolay Kuzmich
Laboratory of Drug Safety, Smorodintsev Research Institute of Influenza, WHO National Influenza Centre of Russia, 15/17 Professor Popov Street, 197376 Saint-Petersburg, Russia
Elena Andresyuk
World-Class Research Center “Digital Biodesign and Personalized Healthcare”, I.M. Sechenov First Moscow State Medical University, 8/2 Trubetskaya Street, 119991 Moscow, Russia
Yuri Porozov
World-Class Research Center “Digital Biodesign and Personalized Healthcare”, I.M. Sechenov First Moscow State Medical University, 8/2 Trubetskaya Street, 119991 Moscow, Russia
Vadim Tarasov
Department of Pharmacology, I.M. Sechenov First Moscow State Medical University, 8/2 Trubetskaya Street, 119991 Moscow, Russia
Mikhail Samsonov
Department of Pharmacology, I.M. Sechenov First Moscow State Medical University, 8/2 Trubetskaya Street, 119991 Moscow, Russia
Nina Preferanskaya
Department of Pharmacology, I.M. Sechenov First Moscow State Medical University, 8/2 Trubetskaya Street, 119991 Moscow, Russia
Valery Veselov
Department of Pharmacology, I.M. Sechenov First Moscow State Medical University, 8/2 Trubetskaya Street, 119991 Moscow, Russia
Renad Alyautdin
Department of Pharmacology, I.M. Sechenov First Moscow State Medical University, 8/2 Trubetskaya Street, 119991 Moscow, Russia
PCSK9 has now become an important target to create new classes of lipid-lowering drugs. The prevention of its interaction with LDL receptors allows an increase in the number of these receptors on the surface of the cell membrane of hepatocytes, which leads to an increase in the uptake of cholesterol-rich atherogenic LDL from the bloodstream. The PCSK9 antagonists described in this review belong to different classes of compounds, may have a low molecular weight or belong to macromolecular structures, and also demonstrate different mechanisms of action. The mechanisms of action include preventing the effective binding of PCSK9 to LDLR, stimulating the degradation of PCSK9, and even blocking its transcription or transport to the plasma membrane/cell surface. Although several types of antihyperlipidemic drugs have been introduced on the market and are actively used in clinical practice, they are not without disadvantages, such as well-known side effects (statins) or high costs (monoclonal antibodies). Thus, there is still a need for effective cholesterol-lowering drugs with minimal side effects, preferably orally bioavailable. Low-molecular-weight PCSK9 inhibitors could be a worthy alternative for this purpose.
