Evidence map›Paper›PMID 39929804›Full record

ArticleNature communications2025

Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV.

Lydia S Newton, Clara Gathmann, Sophie Ridewood, Robert J Smith, Andre J Wijaya, Thomas W Hornsby, Kate L Morling, Dara Annett, Riccardo Zenezini Chiozzi, Ann-Kathrin Reuschl and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

17 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
  4. Article
  5. Article
  6. Review
  7. Review
  8. Review
  9. Article
  10. Review
  11. Article
  12. Review
  13. Review
  14. Review
  15. Article
  16. Review
  17. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors.

Lydia S Newton *Division of Infection and Immunity, University College London, London, UK.ORCID http://orcid.org/0009-0002-1706-8346
Clara Gathmann *Wolfson Institute for Biomedical Research, University College London, London, UK.
Sophie RidewoodDivision of Infection and Immunity, University College London, London, UK.
Robert J SmithWolfson Institute for Biomedical Research, University College London, London, UK.ORCID http://orcid.org/0000-0002-0003-7132
Andre J WijayaCentre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK.ORCID http://orcid.org/0009-0006-0378-376X
Thomas W HornsbyWolfson Institute for Biomedical Research, University College London, London, UK.
Kate L MorlingDivision of Infection and Immunity, University College London, London, UK.ORCID http://orcid.org/0000-0002-2343-3410
Dara AnnettDivision of Infection and Immunity, University College London, London, UK.
Riccardo Zenezini ChiozziUniversity College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London, London, UK.ORCID http://orcid.org/0000-0003-3904-5532
Ann-Kathrin ReuschlDivision of Infection and Immunity, University College London, London, UK.ORCID http://orcid.org/0000-0002-1459-3519
Morten L GovasliDivision of Infection and Immunity, University College London, London, UK.
Ying Ying TanDivision of Infection and Immunity, University College London, London, UK.
Lucy G ThorneDivision of Infection and Immunity, University College London, London, UK.ORCID http://orcid.org/0000-0001-7358-6047
Clare JollyDivision of Infection and Immunity, University College London, London, UK.ORCID http://orcid.org/0000-0002-4603-2281
Konstantinos ThalassinosUniversity College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London, London, UK.ORCID http://orcid.org/0000-0001-5072-8428
Alessio CiulliCentre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK.ORCID http://orcid.org/0000-0002-8654-1670
Greg J TowersDivision of Infection and Immunity, University College London, London, UK. g.towers@ucl.ac.uk.ORCID http://orcid.org/0000-0002-7707-0264
David L SelwoodWolfson Institute for Biomedical Research, University College London, London, UK. d.selwood@ucl.ac.uk.ORCID http://orcid.org/0000-0002-6817-5064

Funding

Rosetrees Trust ID2020/100020Wellcome Trust 214344Wellcome Trust 223065Wellcome Trust (Wellcome) 204841/Z/16/Z
6 · The paper itself

Abstract

Targeting host proteins that are crucial for viral replication offers a promising antiviral strategy. We have designed and characterised antiviral PROteolysis TArgeting Chimeras (PROTACs) targeting the human protein cyclophilin A (CypA), a host cofactor for unrelated viruses including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The PROTAC warheads are based on fully synthetic macrocycles derived from sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporine A. Our Cyp-PROTACs decrease CypA levels in cell lines and primary human cells and have high specificity for CypA confirmed by proteomics experiments. Critically, CypA degradation facilitates improved antiviral activity against HIV-1 in primary human CD4+ T cells compared to the non-PROTAC parental inhibitor, at limiting inhibitor concentrations. Similarly, we observe antiviral activity against HCV replicon in a hepatoma cell line. We propose that CypA-targeting PROTACs inhibit viral replication potently and anticipate reduced evolution of viral resistance and broad efficacy against unrelated viruses. Furthermore, they provide powerful tools for probing cyclophilin biology.

Indexed as

Antiviral AgentsCyclophilin AHepacivirusHIV-1Macrocyclic CompoundsCD4-Positive T-LymphocytesCell Line, TumorHumansLactonesProteolysisProteolysis Targeting ChimeraSpiro CompoundsVirus ReplicationAntiviral AgentsCyclophilin ALactonesMacrocyclic CompoundsProteolysis Targeting Chimerasanglifehrin ASpiro Compounds

Identifiers

PMID39929804
PMCPMC11811207

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.