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A Fluorescence-based Protocol for Preliminary Screening of Protein Synthesis Inhibitors from Natural Sources
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Beyond sequence similarity: toward function-based screening of nucleic acid synthesis.

Gary R Abel1,2, Tessa Alexanian3, Craig Bartling4

  • 1Fourth Eon Bio, San Diego, CA, United States.

Frontiers in Bioengineering and Biotechnology
|June 1, 2026
PubMed
Summary

New screening methods are needed for synthetic nucleic acids to address biosecurity risks from AI-designed biological sequences. Function-based screening can detect hazardous functions, complementing traditional sequence similarity approaches.

Keywords:
DNA synthesis screeningbiological foundation modelsbiosecurityfunction-based screeningprotein function prediction

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Area of Science:

  • Biotechnology
  • Biosecurity
  • Bioinformatics

Background:

  • Synthetic nucleic acids are crucial for biotechnology but pose dual-use risks.
  • Current screening relies on sequence similarity, which may fail against AI-generated sequences.
  • AI can decouple biological function from known sequences, evading detection.

Purpose of the Study:

  • To highlight the need for function-based screening of synthetic nucleic acids.
  • To assess the feasibility of function-based screening for detecting hazardous biological functions.
  • To propose a framework for implementing function-based screening.

Main Methods:

  • Examined the feasibility of function-based screening, focusing initially on proteins.
  • Proposed a framework for implementation, starting with toxins and progressing to complex functions.
  • Discussed challenges and outlined a research and development strategy.

Main Results:

  • Biologically functional proteins are constrained by biophysical and biochemical requirements, making them modelable.
  • Function-based screening can detect hazardous sequences irrespective of similarity to known agents.
  • A phased implementation framework is proposed, starting with toxins.

Conclusions:

  • Function-based screening is a necessary complement to sequence-based methods for biosecurity.
  • Modeling biophysical and biochemical constraints is key to feasible function-based screening.
  • Further research and development are required to address challenges in function-based screening.