# Development of Lipopeptides as Orthoflavivirin Inhibitors with Low Micromolar Broad-Spectrum Antiorthoflaviviral Activity

## TL;DR

Researchers developed lipopeptides that inhibit orthoflaviviruses like dengue and Zika with low toxicity and good drug properties.

## Contribution

A novel lipopeptide scaffold with broad-spectrum antiorthoflaviviral activity and favorable pharmacokinetics is introduced.

## Key findings

- Lipopeptides 73 and 79 inhibited DENV2, WNV, and ZIKV with low micromolar potency and no significant cytotoxicity.
- Compound 73 showed good pharmacokinetic stability and tolerability in mice after multiple administration routes.
- The N-palmitoyl group was identified as essential for effective protease inhibition.

## Abstract

Orthoflaviviral infections
increasingly impact the global
population;
no specific therapeutic treatments are available. The orthoflaviviral
protease NS2B-NS3 is a promising target for antiviral drug development.
Here, we present the design, synthesis, structure–activity
relationship (SAR), and in vivo PK study of a novel lipopeptide scaffold
emerging from exploration of the previously investigated polycationic
geminoids 4–6. The N-palmitoyl
moiety is essential for protease inhibition; optimization of the peptide
sequence led to lipopeptides 73 and 79,
which selectively inhibited dengue virus (DENV2) NS2B-NS3 and exhibited
low micromolar antiviral potency in DENV2-, West Nile virus (WNV)-,
and Zika virus (ZIKV)-infected cells without significant cytotoxicity.
Compound 73 (Palmitoyl-Lys-Ala-d-Ala-Lys-NH2) demonstrated a favorable in vivo pharmacokinetic profile
in BALB/c mice following intravenous (IV), intraperitoneal (IP), and
subcutaneous (SC) administration, showing stability and good tolerability.
Herein, we detail the SAR of the lipopeptide scaffold and suggest
its potential for in vivo therapeutic application administered 20
mg/kg subcutaneously b.i.d..