---
title: "Diimide and Hydrazone Scaffolds as Novel LRAs for HIV-1 Shock-and-Kill Strategies"
id: "pubmed-42735590"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42735590"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42735590/"
doi: "10.1016/j.bbrc.2026.154580"
published_at: "2026-10-22T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Diimide and Hydrazone Scaffolds as Novel LRAs for HIV-1 Shock-and-Kill Strategies
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42735590
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42735590/)
- **DOI:** [10.1016/j.bbrc.2026.154580](https://doi.org/10.1016%2Fj.bbrc.2026.154580)
- **Published At:** 2026-10-22T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The investigators screened a small-molecule library in monocytic and CD4+ T cell lines latently infected with **HIV-1** and previously identified two lead latency-reversing agent (LRA) candidates, labeled #C1 and #C3. - Based on structural similarity, the study team characterized two additional derivatives, compounds #C2 and #C4; #C1 and #C2 contain **diimide** scaffolds, while #C3 and #C4 contain **hydrazone** scaffolds. - In J-Lat 10.6 model cells, all four compounds enhanced LRA activity when combined with either **JQ1** or protein kinase C (PKC) activators, with evidence of synergy reported by the authors. - Compound #C4 plus JQ1 produced measurable reactivation in J-Lat 10.6 cells that were poorly responsive to JQ1 alone, indicating additive or synergistic interaction in that model. - Ex vivo assays using purified CD4+ T cells from ART-suppressed donors showed that #C4 elicited a statistically significant, donor-matched increase in **HIV-1** transcription (paired t-test P = 0.0137, n = 8); JQ1 did not reach significance in the same paired analysis despite a similar mean magnitude. - RNA-sequencing performed by the study team indicated that #C4, JQ1 and PKC activators operate through distinct molecular mechanisms to mediate latency reversal. - The abstract reports these mechanistic differences and donor-level activity, but the source did not include full methodological details, dosing regimens, sample-size breakdown beyond the paired analysis (n = 8), nor safety or cytotoxicity data in the abstract. - The authors conclude these compounds represent a structurally novel class of LRA candidates; the abstract does not present final in vivo efficacy, clinical development steps, or complete toxicity profiling.
## Clinical Analysis & Structured Key Points
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Epub 2026 Sep 11. # Identification of novel diimide and hydrazone scaffolds for synergistic HIV-1 shock and kill strategies [Sayaka Sukegawa](https://pubmed.ncbi.nlm.nih.gov/?term=Sukegawa+S&cauthor_id=42735590)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-1 "Department of Molecular Virology, Institute of Science Tokyo, Tokyo, 113-8519, Japan; Center for Infectious Disease Education and Analysis \(TCIDEA\), Institute of Science Tokyo, Tokyo, 113-8519, Japan. Electronic address: sayaka.sukegawa.molv@tmd.ac.jp."), [Kouki Matsuda](https://pubmed.ncbi.nlm.nih.gov/?term=Matsuda+K&cauthor_id=42735590)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-2 "Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan."), [Haruki Kitamura](https://pubmed.ncbi.nlm.nih.gov/?term=Kitamura+H&cauthor_id=42735590)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-3 "Viral Biochemistry Section, Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD, 20892-0460, USA."), [Kousuke Tanimoto](https://pubmed.ncbi.nlm.nih.gov/?term=Tanimoto+K&cauthor_id=42735590)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-4 "Department of High-risk Infectious Disease Control, Institute of Science Tokyo, Tokyo, 113-8519, Japan."), [Chieko Fujisaki](https://pubmed.ncbi.nlm.nih.gov/?term=Fujisaki+C&cauthor_id=42735590)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-5 "Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8544, Japan."), [Takuya Kobayakawa](https://pubmed.ncbi.nlm.nih.gov/?term=Kobayakawa+T&cauthor_id=42735590)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-6 "Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, 113-8519, Japan."), [Tomoya Tsukitani](https://pubmed.ncbi.nlm.nih.gov/?term=Tsukitani+T&cauthor_id=42735590)[ 7 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-7 "Department of Molecular Virology, Institute of Science Tokyo, Tokyo, 113-8519, Japan."), [Hiroki Yoshino](https://pubmed.ncbi.nlm.nih.gov/?term=Yoshino+H&cauthor_id=42735590)[ 7 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-7 "Department of Molecular Virology, Institute of Science Tokyo, Tokyo, 113-8519, Japan."), [Hirokazu Tamamura](https://pubmed.ncbi.nlm.nih.gov/?term=Tamamura+H&cauthor_id=42735590)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-6 "Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, 113-8519, Japan."), [Kenji Maeda](https://pubmed.ncbi.nlm.nih.gov/?term=Maeda+K&cauthor_id=42735590)[ 8 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-8 "Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan. Electronic address: kmaeda@kufm.kagoshima-u.ac.jp."), [Hiroaki Takeuchi](https://pubmed.ncbi.nlm.nih.gov/?term=Takeuchi+H&cauthor_id=42735590)[ 9 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#full-view-affiliation-9 "Department of High-risk Infectious Disease Control, Institute of Science Tokyo, Tokyo, 113-8519, Japan; Center for Infectious Disease Education and Analysis \(TCIDEA\), Institute of Science Tokyo, Tokyo, 113-8519, Japan. Electronic address: htake.molv@tmd.ac.jp.") Affiliations Expand ### Affiliations * 1 Department of Molecular Virology, Institute of Science Tokyo, Tokyo, 113-8519, Japan; Center for Infectious Disease Education and Analysis (TCIDEA), Institute of Science Tokyo, Tokyo, 113-8519, Japan. Electronic address: sayaka.sukegawa.molv@tmd.ac.jp. * 2 Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan. * 3 Viral Biochemistry Section, Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD, 20892-0460, USA. * 4 Department of High-risk Infectious Disease Control, Institute of Science Tokyo, Tokyo, 113-8519, Japan. * 5 Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8544, Japan. * 6 Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, 113-8519, Japan. * 7 Department of Molecular Virology, Institute of Science Tokyo, Tokyo, 113-8519, Japan. * 8 Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan. Electronic address: kmaeda@kufm.kagoshima-u.ac.jp. * 9 Department of High-risk Infectious Disease Control, Institute of Science Tokyo, Tokyo, 113-8519, Japan; Center for Infectious Disease Education and Analysis (TCIDEA), Institute of Science Tokyo, Tokyo, 113-8519, Japan. Electronic address: htake.molv@tmd.ac.jp. * PMID: **42735590** * DOI: [ 10.1016/j.bbrc.2026.154580 ](https://doi.org/10.1016/j.bbrc.2026.154580) Free article Item in Clipboard # Identification of novel diimide and hydrazone scaffolds for synergistic HIV-1 shock and kill strategies Sayaka Sukegawa et al. Biochem Biophys Res Commun. 2026. Free article Show details Display options Display options Format Abstract PubMed PMID Biochem Biophys Res Commun Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Biochem+Biophys+Res+Commun%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Biochem+Biophys+Res+Commun%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42735590/) . 2026 Oct 22:836:154580. doi: 10.1016/j.bbrc.2026.154580. Epub 2026 Sep 11. ### Authors [Sayaka Sukegawa](https://pubmed.ncbi.nlm.nih.gov/?term=Sukegawa+S&cauthor_id=42735590)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-1 "Department of Molecular Virology, Institute of Science Tokyo, Tokyo, 113-8519, Japan; Center for Infectious Disease Education and Analysis \(TCIDEA\), Institute of Science Tokyo, Tokyo, 113-8519, Japan. Electronic address: sayaka.sukegawa.molv@tmd.ac.jp."), [Kouki Matsuda](https://pubmed.ncbi.nlm.nih.gov/?term=Matsuda+K&cauthor_id=42735590)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-2 "Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan."), [Haruki Kitamura](https://pubmed.ncbi.nlm.nih.gov/?term=Kitamura+H&cauthor_id=42735590)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-3 "Viral Biochemistry Section, Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD, 20892-0460, USA."), [Kousuke Tanimoto](https://pubmed.ncbi.nlm.nih.gov/?term=Tanimoto+K&cauthor_id=42735590)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-4 "Department of High-risk Infectious Disease Control, Institute of Science Tokyo, Tokyo, 113-8519, Japan."), [Chieko Fujisaki](https://pubmed.ncbi.nlm.nih.gov/?term=Fujisaki+C&cauthor_id=42735590)[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-5 "Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8544, Japan."), [Takuya Kobayakawa](https://pubmed.ncbi.nlm.nih.gov/?term=Kobayakawa+T&cauthor_id=42735590)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-6 "Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, 113-8519, Japan."), [Tomoya Tsukitani](https://pubmed.ncbi.nlm.nih.gov/?term=Tsukitani+T&cauthor_id=42735590)[ 7 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-7 "Department of Molecular Virology, Institute of Science Tokyo, Tokyo, 113-8519, Japan."), [Hiroki Yoshino](https://pubmed.ncbi.nlm.nih.gov/?term=Yoshino+H&cauthor_id=42735590)[ 7 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-7 "Department of Molecular Virology, Institute of Science Tokyo, Tokyo, 113-8519, Japan."), [Hirokazu Tamamura](https://pubmed.ncbi.nlm.nih.gov/?term=Tamamura+H&cauthor_id=42735590)[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-6 "Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, 113-8519, Japan."), [Kenji Maeda](https://pubmed.ncbi.nlm.nih.gov/?term=Maeda+K&cauthor_id=42735590)[ 8 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-8 "Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan. Electronic address: kmaeda@kufm.kagoshima-u.ac.jp."), [Hiroaki Takeuchi](https://pubmed.ncbi.nlm.nih.gov/?term=Takeuchi+H&cauthor_id=42735590)[ 9 ](https://pubmed.ncbi.nlm.nih.gov/42735590/#short-view-affiliation-9 "Department of High-risk Infectious Disease Control, Institute of Science Tokyo, Tokyo, 113-8519, Japan; Center for Infectious Disease Education and Analysis \(TCIDEA\), Institute of Science Tokyo, Tokyo, 113-8519, Japan. Electronic address: htake.molv@tmd.ac.jp.") ### Affiliations * 1 Department of Molecular Virology, Institute of Science Tokyo, Tokyo, 113-8519, Japan; Center for Infectious Disease Education and Analysis (TCIDEA), Institute of Science Tokyo, Tokyo, 113-8519, Japan. Electronic address: sayaka.sukegawa.molv@tmd.ac.jp. * 2 Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan. * 3 Viral Biochemistry Section, Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD, 20892-0460, USA. * 4 Department of High-risk Infectious Disease Control, Institute of Science Tokyo, Tokyo, 113-8519, Japan. * 5 Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 890-8544, Japan. * 6 Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, 113-8519, Japan. * 7 Department of Molecular Virology, Institute of Science Tokyo, Tokyo, 113-8519, Japan. * 8 Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan. Electronic address: kmaeda@kufm.kagoshima-u.ac.jp. * 9 Department of High-risk Infectious Disease Control, Institute of Science Tokyo, Tokyo, 113-8519, Japan; Center for Infectious Disease Education and Analysis (TCIDEA), Institute of Science Tokyo, Tokyo, 113-8519, Japan. Electronic address: htake.molv@tmd.ac.jp. * PMID: **42735590** * DOI: [ 10.1016/j.bbrc.2026.154580 ](https://doi.org/10.1016/j.bbrc.2026.154580) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## Abstract Combination antiretroviral therapy (ART) is currently the standard-of-care to control HIV replication in infected individuals. However, since this treatment mainly targets viral enzymes, the presence of latently-infected reservoirs and the emergence of drug resistance remain major barriers to viral eradication. To overcome this, a "Shock and Kill" approach has been developed, using "latency-reversing agents" (LRAs) to activate latent proviruses ("shock"), leading to viral elimination by ART and immune-mediated clearance ("kill"). We previously screened a small-molecule library on monocytic and CD4+ T cell lines latently infected with HIV, and identified two novel LRA candidates (compounds #C1 and #C3). Based on their structural features, we now identified two related derivatives, compounds #C2 and #C4. Compounds #C1 and #C2 possess diimide structures, whereas #C3 and #C4 have hydrazone structures. All four compounds synergistically enhanced LRA activity when combined with JQ1 or PKC activators in J-Lat 10.6 cells. Notably, combining #C4 with JQ1 further enhanced HIV reactivation showing limited responsiveness to JQ1 alone in J-Lat 10.6 model cells. In ex vivo purified CD4+ T cells from ART-suppressed individuals, #C4 elicited a statistically significant, donor-matched increase in HIV-1 transcription (ratio paired t-test, P = 0.0137, n = 8), whereas JQ1 did not reach significance under the same paired analysis despite a comparable mean magnitude. Notably, #C4 additionally induced measurable reactivation in donors with limited responsiveness to JQ1 alone. RNA-sequencing analyses indicated that compound #C4, JQ1 and PKC activators mediated LRA activity through distinct molecular mechanisms. Collectively, these findings delineate a structurally novel class of LRA candidates that eng
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