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Review

Advances in biocatalytic and chemoenzymatic synthesis of nucleoside analogues

ORCID Icon & ORCID Icon
Pages 355-364 | Received 14 Dec 2021, Accepted 04 Feb 2022, Published online: 17 Feb 2022

Figures & data

Figure 1. Examples of nucleoside analogue drugs.

Figure 1. Examples of nucleoside analogue drugs.

Scheme 1. Enzymatic synthesis of α-d-pentose 1-phosphates using a thermostable pyrimidine nucleoside phosphorylase; isolation as Ba2+ salt form facilitates purification by precipitation and gram-scale access; TNP = thymidine nucleoside phosphorylase.

Scheme 1. Enzymatic synthesis of α-d-pentose 1-phosphates using a thermostable pyrimidine nucleoside phosphorylase; isolation as Ba2+ salt form facilitates purification by precipitation and gram-scale access; TNP = thymidine nucleoside phosphorylase.

Scheme 2. Diversification of 4’-Me substituted nucleosides using the nucleoside phosphorylase TtDyNP; transglycosylation under thermodynamic reaction control enables the insertion of pyrimidines or purines; R = Me, F, Br, I, CF3; R1 = NH2 or OH; R2 = NH2, H or Cl.

Scheme 2. Diversification of 4’-Me substituted nucleosides using the nucleoside phosphorylase TtDyNP; transglycosylation under thermodynamic reaction control enables the insertion of pyrimidines or purines; R = Me, F, Br, I, CF3; R1 = NH2 or OH; R2 = NH2, H or Cl.

Scheme 3. A) Nucleoside salvage pathway enzymes for the degradation of inosine. B) An engineered pathway for didanosine production. C) Biocatalytic synthesis of islatravir. Engineered enzymes are shown in blue, accessory enzymes in red. RK = ribokinase, PPM = phosphopentomutase, PNP = purine nucleoside phosphorylase, PanK = pantothenate kinase, DERA = deoxyribose 5-phosphate aldolase, PK = pyruvate kinase, AK = adenylate kinase, GOase = galactose oxidase, HRP = horseradish peroxidase.

Scheme 3. A) Nucleoside salvage pathway enzymes for the degradation of inosine. B) An engineered pathway for didanosine production. C) Biocatalytic synthesis of islatravir. Engineered enzymes are shown in blue, accessory enzymes in red. RK = ribokinase, PPM = phosphopentomutase, PNP = purine nucleoside phosphorylase, PanK = pantothenate kinase, DERA = deoxyribose 5-phosphate aldolase, PK = pyruvate kinase, AK = adenylate kinase, GOase = galactose oxidase, HRP = horseradish peroxidase.

Scheme 4. Chemoenzymatic synthesis of molnupiravir 12. MTRk = 5-S-methylthirbose kinase, UP = uridine phosphorylase, AcK = acetate kinase, PO = pyruvate oxidase, ATP = adenosine triphosphate.

Scheme 4. Chemoenzymatic synthesis of molnupiravir 12. MTRk = 5-S-methylthirbose kinase, UP = uridine phosphorylase, AcK = acetate kinase, PO = pyruvate oxidase, ATP = adenosine triphosphate.