ROME Therapeutics Announces Publication of First Crystal Structure of a Human Endogenous Reverse Transcriptase in PNAS

Study reveals first-ever structure of a non-viral endogenous reverse transcriptase (eRT)

Human endogenous retrovirus-K (HERV-K) RT shows striking similarity to HIV RT

Findings enable structure-based drug discovery for eRTs

Excerpt from the Press Release:

CAMBRIDGE, Mass.–(BUSINESS WIRE)–ROME Therapeutics, a biotechnology company harnessing the power of the dark genome for drug development, today announced 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). The structure unlocks therapeutic opportunities for RT inhibitors in cancer, autoimmune and neurodegenerative diseases.

“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.

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