GS-9822, a Preclinical LEDGIN Candidate, Displays a Block-and-Lock Phenotype in Cell Culture
Open accessAbstract
The ability of HIV to integrate into the host genome and establish latent reservoirs is the main hurdle preventing an HIV cure. LEDGINs are small-molecule integrase inhibitors that target the binding pocket of LEDGF/p75, a cellular cofactor that substantially contributes to HIV integration site selection.
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Several ALLINIs have low-nanomolar potency against HIV-1 replication in vitro, though none have advanced to clinical trials.
“Although ALLINIs have yet to advance in clinical trials, several compounds display exquisite low-nM potencies to inhibit HIV-1 replication in vitro172,180,182,183.”
From Structure and function of retroviral integrase (2022) · cites this paper as [183]
The Introduction reports low-nanomolar in vitro antiviral activity for BI224436, supporting the potency portion of the claim. But it also says BI224436 was the first LEDGIN to advance into phase Ia clinical trials, directly contradicting the assertion that none had advanced to clinical trials. No page number is available in our copy. (LLM, conf=0.94)
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Experimental — accuracy not yet measuredProviruses resulting from ALLINI treatment are marginally recalcitrant to latency reversal agents, suggesting ALLINIs could reduce the size and reactivation potential of the latent reservoir.
“Resultant proviruses were marginally recalcitrant to transcriptional activation via latency reversal agents183,185, indicating that ALLINIs could potentially be employed as preexposure prophylactic compounds to reduce both the size and reactivation potential of the latent viral reservoir.”
From Structure and function of retroviral integrase (2022) · cites this paper as [183]
The reactivation-results section (page unavailable) reports that proviruses formed during GS-9822 or CX14442 treatment had a dose-dependent reduction in the reactivatable latent fraction after TNFα stimulation. The Discussion proposes early treatment to induce a more latent reservoir, but it does not establish preexposure prophylaxis or show that ALLINIs reduce the size of the latent reservoir. Those parts of the citing sentence go beyond the cell-culture findings. (LLM, conf=0.84)
Experimental — accuracy not yet measuredALLINIs have proven too toxic for in-depth clinical trials despite high potency.
“Although highly potent compounds, ALLINIs to date have proven too toxic for in-depth clinical trials183, warranting attempts to develop safer compounds that can hopefully advance to the clinic.”
From Structure and function of retroviral integrase (2022) · cites this paper as [183]
The Introduction and Discussion report that potent GS-9822 had urothelial toxicity in monkeys, halting its further advancement. They do not establish that ALLINIs as a class have proven too toxic for in-depth clinical trials: the Introduction says BI224436 reached a phase Ia trial without safety concerns at the reported doses, and the Discussion describes another candidate with no significant toxicity reported in rats or dogs. Page numbers are unavailable in our copy. (LLM, conf=0.87)
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References 83 · Cited by 35
- Authors
- Bruggemans, A., Vansant, G., Balakrishnan, M., Mitchell, M. L., Cai, R., Christ, F., & Debyser, Z.
- Affiliations
- KU Leuven (BE)
- Gilead Sciences (United States) (US)
- Corresponding author
- Debyser, Zeger
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2021-04-19
- Volume
- 65
- Issue
- 5
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC8092873
- OpenAlex
- W3132662822
- Cited by
- 35
- References
- 83
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 2
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Funders
- Fonds Wetenschappelijk Onderzoek (1134117N, G0A5316N, SBO-Saphir)
- Onderzoeksraad, KU Leuven (C14/17/095-3M170311)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- LEDGF/p75, HIV integrase inhibitors, HIV latency, latent reservoir, latency reversal, antiviral potency, epigenetic landscape, functional cure, HIV cure
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