Sterile alpha motif and HD domain-containing protein 1 (SAMHD1)

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is an enzyme encoded by the SAMHD1 gene in humans. It catalyzes the hydrolysis of deoxynucleoside triphosphates (dNTPs) into deoxynucleosides and inorganic triphosphate, thereby tightly regulating the intracellular dNTP pool. This activity is crucial for limiting the availability of nucleotides required for viral reverse transcription, making SAMHD1 a cell-intrinsic restriction factor against HIV-1 and other retroviruses. SAMHD1 is also involved in maintaining genome stability and facilitating DNA double-strand break repair, independent of its dNTPase activity. Mutations in SAMHD1 are linked to the autoimmune disease Aicardi-Goutières syndrome and chronic lymphocytic leukemia. While no clinically approved therapies directly target SAMHD1 as of September 2025, its function is manipulated by certain lentiviral proteins, such as Vpx, and it is being explored as a potential target for modulating immune responses and viral replication.

Other names

Deoxynucleoside triphosphate triphosphohydrolase SAMHD1MOP5dNTPaseDCIPhSAMHD1SBBI88Mg11HDDC1AGS5Aicardi-Goutières syndrome 5 proteinMonocyte protein 5Dendritic cell-derived IFNG-induced proteinHD domain containing 1

Inhibitors would modulate (usually inhibit) SAMHD1 dNTPase activity, increasing dNTP levels and potentiating viral replication or DNA synthesis.\nActivators or mimetics may enhance dNTPase function, reducing nucleotide pools and restricting viral replication.\nIndirect modulation via the Vpx protein (in HIV-2 and related viruses) targets SAMHD1 for proteasomal degradation, lifting its restriction on HIV-1 replication.