Statins: 50 years old and with new surprises in store

Inspired by Fleming

Biosynthesis of sterols plays an important role in many biological systems. Cholesterol was discovered in gallstones in 1789 and was the first sterol to be identified (3). Akira Endo hypothesised that since sterols are important biological substances, some cells must contain synthesis inhibitors that can prevent the growth of other cells that would threaten their proliferation (1, 2). He speculated that there could be an analogy to antibiotics (penicillin and streptomycin) that are produced by certain fungal species. The hydroxymethylglutaryl coenzyme A reductase (HMG-CoA reductase) enzyme catalyses a rate-limiting step in the synthesis of sterols, including cholesterol (4).

Inspired by Alexander Fleming's (1881–1955) success with penicillin-producing fungi, and equipped with a newly developed method for large-scale assays of HMG-CoA reductase activity, Endo and his colleagues at the company Sankyo began searching various fungal species in 1971 for inhibitors of this enzyme (1, 2). Akira Endo was awarded the European Society of Cardiology 2021 Gold Medal for this pioneering work (5). Over a two-year period, he and his colleagues tested approximately 6000 species of fungi. In 1972, they identified a potent and irreversible HMG-CoA reductase inhibitor – citrinin, which was already known and had been shown to be nephrotoxic.

In the summer of 1973, they isolated three active inhibitors in cultures from the blue-green mould Penicillium citrinum Pen51. The mould was isolated from rice they had collected from a shop selling grain in Kyoto

They continued their work, and in the summer of 1973, they isolated three active inhibitors in cultures from the blue-green mould Penicillium citrinum Pen51 (1, 2). The mould was isolated from rice they had collected from a shop selling grain in Kyoto. This blue-green mould resembles the fungi that contaminate fruits like oranges and melons. All three substances inhibited cholesterol synthesis both in vitro and in vivo. The researchers continued their study using the most active inhibitor, which was given the name ML-236B, later known as compactin and mevastatin. This was the first statin. This reversible inhibitor of HMG-CoA reductase was structurally determined towards the end of 1973 (1), which is therefore considered the breakthrough year for the discovery of statins.