JE-2147

Summary

JE-2147 (also known as AG‑1776, KNI‑764) is an experimental dipeptide HIV‑1 protease inhibitor belonging to the allophenylnorstatine (APNS) family. Developed as a second‑generation protease inhibitor, it shows picomolar binding affinity for HIV‑1 protease and retains activity against a wide range of wild‑type and multi‑protease‑inhibitor‑resistant HIV strains in vitro. Research is ongoing to improve its pharmacokinetic profile and to explore potential repurposing against other viral proteases such as SARS‑CoV‑2 Mpro.

Mechanism of Action

JE‑2147 binds directly to the active site of HIV‑1 protease, occupying the substrate‑binding pocket and stabilising the flaps in a closed conformation. Structural studies indicate an enthalpically driven interaction, with a flexible P2′ moiety allowing tight accommodation of the enzyme’s catalytic aspartates. This high‑affinity binding (K i ≈ 41 pM) blocks proteolytic processing of viral polyproteins, preventing maturation of infectious virions. Computational work suggests the same scaffold can also engage the catalytic dyad of SARS‑CoV‑2 main protease, although this remains theoretical.

What the Research Shows

In vitro investigations demonstrated that JE‑2147 inhibits HIV‑1, HIV‑2, SIV and clinical isolates with IC50 values of 13–41 nM, showing less than two‑fold loss of potency against multi‑PI‑resistant strains. High‑resolution (1.09 Å) crystal structures revealed an enthalpy‑driven binding mode and identified key flap and dimer‑interface motions. Molecular‑dynamics simulations highlighted a specific resistance mutation (I47V) that reduces inhibitor packing, while broader resistance in clinical isolates required compensatory Gag non‑cleavage‑site mutations. Structure‑metabolism studies showed that para‑substituted analogues avoid glucuronidation and improve pharmacokinetics. A 2023 in silico study reported strong predicted binding of JE‑2147 to SARS‑CoV‑2 Mpro (ΔG_bind ≈ ‑28 kcal/mol). No human safety or efficacy trials have been reported.

Reported Benefits

JE‑2147 exhibits exceptionally high affinity for HIV‑1 protease (picomolar Ki) and maintains potency against viruses that are resistant to all currently approved protease inhibitors. In vitro resistance emergence is slower than with earlier APNS compounds, and structural flexibility of the P2′ group appears to underpin this advantage. Analogue optimisation has produced molecules with better metabolic stability, suggesting the scaffold can be refined for improved drug‑like properties.

Limitations of the Evidence

All data are limited to laboratory and computational studies; no clinical trials or human safety data exist. Resistance can still develop via the I47V protease mutation and through compensatory Gag mutations, indicating that JE‑2147 is not impervious to viral escape. Metabolic glucuronidation of the parent compound remains a concern, and the antiviral activity against SARS‑CoV‑2 is purely predictive. Consequently, its therapeutic potential remains unproven.

Safety Considerations

The abstracts provide no information on toxicity, tolerability, or adverse events in animals or humans. As a research‑only compound, safety has not been established, and any clinical use would require extensive pre‑clinical and clinical evaluation before risk–benefit conclusions could be drawn.

How It Is Administered

JE‑2147 is listed as an orally administered experimental agent. Formulation details are not described in the published literature, and dosing regimens have not been defined for human use.

Routes of Administration

Goals & Uses

• HIV-2 protease inhibitionAntiviralLow
• HIV-1 protease inhibitionAntiviralModerate
• Research tool for protease resistance studiesResearchModerate
• Activity against drug-resistant HIV strainsAntiviralModerate

Contraindications

• Not established for clinical useGeneralHigh

Adverse Effects

• Unknown human safety profileGeneralUnknown

Drug Interactions

• CYP3A4 substrates/inhibitorsLow

Population Constraints

• General populationGeneralAbsolute

Regulatory Status

• European UnionUnapprovedNo marketing authorization; research use only.
• United StatesUnapprovedResearch compound only; no IND or NDA filed as publicly known.
• United KingdomUnapprovedNo regulatory approval; laboratory research compound.

JE-2147 has not received regulatory approval in any jurisdiction. It remains a research/investigational compound used primarily in laboratory studies of HIV protease inhibition and resistance mechanisms.

Evidence & Sources

• Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors
  Journal ArticleLowGatanaga H, et al.2002-01-01T00:00:00.000000Z
• Drug resistance of HIV-1 protease against JE-2147: I47V mutation investigated by molecular dynamics simulation
  Journal ArticleLowBandyopadhyay P, Meher BR2006-01-01T00:00:00.000000Z
• Structure-activity and structure-metabolism relationships of HIV protease inhibitors containing the 3-hydroxy-2-methylbenzoyl-allophenylnorstatine structure
  Journal ArticleLowMimoto T, et al.2004-01-01T00:00:00.000000Z
• Molecular insights to the binding interactions of APNS containing HIV-protease inhibitors against SARS-CoV-2 M(pro): an in silico approach towards drug repurposing
  Journal ArticleLowPurohit P, et al.2023-01-01T00:00:00.000000Z
• Anisotropic dynamics of the JE-2147-HIV protease complex: drug resistance and thermodynamic binding mode examined in a 1.09 A structure
  Journal ArticleLowReiling KK, et al.2002-01-01T00:00:00.000000Z
• JE-2147: a dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1
  Journal ArticleLowYoshimura K, et al.1999-01-01T00:00:00.000000Z

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