On June 30, 2022 ROME Therapeutics, a biotechnology company harnessing the power of the dark genome for drug development, reported a new publication in The Proceedings of the National Academy of Sciences (PNAS) which describes the first-ever X-ray crystallography structure of an endogenous reverse transcriptase – specifically human endogenous retrovirus-K (HERV-K) reverse transcriptase (RT) (Press release, Rome Therapeutics, JUN 30, 2022, View Source [SID1234616418]). The structure unlocks therapeutic opportunities for RT inhibitors in cancer, autoimmune and neurodegenerative diseases.
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"A significant portion of the human genome is made up of endogenous retroviruses, which are associated with a range of serious diseases, including cancer. In this publication, we describe for the first time the crystal structure of an endogenous reverse transcriptase, one known as HERV-K RT, and show that it has remarkable similarities to HIV RT, a well-known tractable drug target," said Dennis Zaller, Ph.D., Chief Scientific Officer of ROME. "This achievement is a milestone in the dark genome field and sheds light on opportunities for structure-based drug design based on established anti-viral targets present in the human genome. This work is the result of a great collaboration between ROME’s exceptional structural biology team and world-leading crystallographers."
Repetitive elements in the genome, such as HERV-K, are frequently over-expressed in cancer and elicit biological viral mimicry responses that can alter the tumor microenvironment. Anti-viral drugs with activity against endogenous retrovirus-derived repeats can have therapeutic benefit, as illustrated by a recent study from ROME’s scientific co-founders published in Cancer Discovery showing that a nucleoside reverse transcriptase inhibitor designed for HIV-1 (3TC) led to clinical benefit in 9 of 32 patients with late-stage colorectal cancer. These findings demonstrate the potential of molecules designed for activity against repeat-encoded targets, such as eRT, the first therapeutic target announced by ROME in November 2021.
"This study marks a significant step forward in our understanding of endogenous retroviruses and how they could be targeted to treat disease," said Eddy Arnold, Ph.D., Resident Faculty Member at the Center for Advanced Biotechnology and Medicine (CABM), Board of Governors Professor of Chemistry and Chemical Biology at Rutgers University and Scientific Advisory Board member at ROME. "Characterizing the structure of HIV RT was a critical turning point in designing novel medicines to combat that deadly virus. Similarly, deeper insights into human endogenous RT could pave the way toward a new class of therapies for cancer and other serious diseases."