The South Caucasus : drama on three stages

James Nixe

Russian patronage over Abkhazia and South Ossetia: implications for conflict resolution

This article applies the concepts of linkage and leverage as developed by Steven Levitsky and Lucan Way and elaborated by Gwendolyn Sasse in the introduction to this special issue of East European Politics to Russia’s involvement with Abkhazia and South Ossetia, the two quasi-independent states in the South Caucasus. Through this re-conceptualisation of the developments in Abkhazia and South Ossetia, combined with new empirical insights, the article aims to increase our understanding of the conflicts in the region, of the involvement of the Russian Federation in particular, and consequently of the prospects of international conflict resolution. Compared to other political entities in the former Soviet Union, Abkhazia and South Ossetia represent an extreme case of Russian linkage and leverage. This article focuses on the period after the Russian–Georgian war in 2008, when Russia recognised the regions’ independence and effectively turned them into Russian protectorates. The economic, intergovernmental, technocratic and social linkages between Russia and the two regions are extraordinarily deep, and they directly undermine the autonomy of the regions. The post-war delegation of Russian cadres and institutional and legislative diffusion creates additional linkages underpinning Russian leverage.History and International Relation

Engineering Antibody Reactivity for Efficient Derivatization to Generate Na_V1.7 Inhibitory GpTx‑1 Peptide–Antibody Conjugates

The voltage-gated sodium channel Na_V1.7 is a genetically validated pain target under investigation for the development of analgesics. A therapeutic with a less frequent dosing regimen would be of value for treating chronic pain; however functional Na_V1.7 targeting antibodies are not known. In this report, we describe Na_V1.7 inhibitory peptide–antibody conjugates as an alternate construct for potential prolonged channel blockade through chemical derivatization of engineered antibodies. We previously identified Na_V1.7 inhibitory peptide GpTx-1 from tarantula venom and optimized its potency and selectivity. Tethering GpTx-1 peptides to antibodies bifunctionally couples FcRn-based antibody recycling attributes to the Na_V1.7 targeting function of the peptide warhead. Herein, we conjugated a GpTx-1 peptide to specific engineered cysteines in a carrier anti-2,4-dinitrophenol monoclonal antibody using polyethylene glycol linkers. The reactivity of 13 potential cysteine conjugation sites in the antibody scaffold was tuned using a model alkylating agent. Subsequent reactions with the peptide identified cysteine locations with the highest conversion to desired conjugates, which blocked Na_V1.7 currents in whole cell electrophysiology. Variations in attachment site, linker, and peptide loading established design parameters for potency optimization. Antibody conjugation led to <i>in vivo</i> half-life extension by 130-fold relative to a nonconjugated GpTx-1 peptide and differential biodistribution to nerve fibers in wild-type but not Na_V1.7 knockout mice. This study describes the optimization and application of antibody derivatization technology to functionally inhibit Na_V1.7 in engineered and neuronal cells