9EC2

Crystal structure of SAMHD1 dimer bound to an inhibitor obtained from high-throughput chemical tethering to the guanine antiviral acyclovir

This is a non-PDB format compatible entry.

Summary for 9EC2

• Entry DOI: 10.2210/pdb9ec2/pdb
• Related: 8GB1
• Descriptor: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1, N-[5-({2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl}amino)-5-oxopentyl]-4,7-dibromo-3-hydroxynaphthalene-2-carboxamide, FE (III) ION, ... (4 entities in total)
• Functional Keywords: inhibitors of samhd1 obtained from high-throughput chemical tethering to the guanine antiviral acyclovir, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 242046.14

Authors

Egleston, M.,Dong, L.,Howlader, A.H.,Bhat, S.,Orris, B.,Lopez-Rovira, L.M.,Bianchet, M.A.,Greenberg, M.M.,Stivers, J.T. (deposition date: 2024-11-13, release date: 2025-03-12, Last modification date: 2025-03-19)

Primary citation

Egleston, M.,Bhat, S.,Howlader, A.H.,Bianchet, M.A.,Liu, Y.,Lopez Rovira, L.M.,Smith, B.,Greenberg, M.M.,Stivers, J.T.
Inhibitors of SAMHD1 Obtained from Chemical Tethering to the Guanine Antiviral Acyclovir.
Biochemistry, 64:1109-1120, 2025

PubMed Abstract: Sterile alpha motif histidine-aspartate domain protein 1 (SAMHD1) is an enzyme with diverse activities. Its dNTPase activity degrades all canonical dNTPs and many anticancer nucleoside drugs, while its single-stranded nucleic acid binding activity promotes DNA repair and RNA homeostasis in cells. These functions require guanine nucleotide binding to a specific allosteric site (A1) on the enzyme. We previously described how the activities of SAMHD1 could be inhibited in vitro with fragment-based inhibitor design, using dGMP as a targeting fragment for the A1 site. However, these dGMP-tethered inhibitors had poor cell permeability due to the charged guanine monophosphate group. Here, we describe a new approach where the amino form of the guanine acyclic nucleoside acyclovir (NH-ACV) is used as the targeting fragment, allowing facile coupling to activated carboxylic acids (R-COOH), either directly or using linkers. This approach generates a neutral amide instead of charged monophosphate attachment points. High-throughput screening of a ∼375 compound carboxylic acid library identified two compounds (, ) with similar micromolar affinities for SAMHD1. Compound was obtained by direct coupling to NH-ACV, while compound used a five-carbon linker. Both inhibitors had the same dibromonaphthol component from the carboxylic acid library screen. A crystal structure of a complex between SAMHD1 and combined with computational models of bound suggest how the dibromonaphthol promotes binding. The findings establish that guanine-based inhibitors targeting the A1 site do not require nucleotide or cyclic nucleoside structural elements. This guanine site targeting strategy is highly amenable to further chemical optimization.

PubMed: 39989431
DOI: 10.1021/acs.biochem.4c00854

Experimental method

X-RAY DIFFRACTION (2.72 Å)