ROME Therapeutics, Boston, MA 02215.
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Proc Natl Acad Sci U S A. 2022 Jul 5;119(27):e2200260119. doi: 10.1073/pnas.2200260119. Epub 2022 Jun 30.
Human endogenous retroviruses (HERVs) comprise nearly 8% of the human genome and are derived from ancient integrations of retroviruses into the germline. The biology of HERVs is poorly defined, but there is accumulating evidence supporting pathological roles in diverse diseases, such as cancer, autoimmune, and neurodegenerative diseases. Functional proteins are produced by HERV-encoded genes, including reverse transcriptases (RTs), which could be a contributor to the pathology attributed to aberrant HERV-K expression. To facilitate the discovery and development of HERV-K RT potent and selective inhibitors, we expressed active HERV-K RT and determined the crystal structure of a ternary complex of this enzyme with a double-stranded DNA substrate. We demonstrate a range of RT inhibition with antiretroviral nucleotide analogs, while classic nonnucleoside analogs do not inhibit HERV-K RT. Detailed comparisons of HERV-K RT with other known RTs demonstrate similarities to diverse RT families and a striking similarity to the HIV-1 RT asymmetric heterodimer. Our analysis further reveals opportunities for selective HERV-K RT inhibition.
人类内源性逆转录病毒 (HERV) 约占人类基因组的 8%，是由逆转录病毒远古时期整合到生殖细胞系中产生的。HERV 的生物学特性尚未完全明确，但越来越多的证据表明其在多种疾病（如癌症、自身免疫性疾病和神经退行性疾病）中具有病理性作用。HERV 编码基因可产生功能蛋白，包括逆转录酶 (RT)，这可能是导致异常 HERV-K 表达所致病理的一个因素。为了促进 HERV-K RT 有效且选择性抑制剂的发现和开发，我们表达了活性 HERV-K RT，并确定了该酶与双链 DNA 底物形成的三元复合物的晶体结构。我们用抗逆转录病毒核苷酸类似物证明了对 RT 的广泛抑制作用，而经典的非核苷类似物则不能抑制 HERV-K RT。对 HERV-K RT 与其他已知 RT 的详细比较表明，它与多种 RT 家族具有相似性，并且与 HIV-1 RT 不对称异二聚体具有惊人的相似性。我们的分析进一步揭示了选择性抑制 HERV-K RT 的机会。
