After several attempts to find a political solution, De Mistura in July proposed a fresh approach whereby Syrians would take part in "thematic" working groups.
The envoy met with the heads of these groups over the last two days, seeking to "set the stage for a Syrian agreement to end the conflict," De Mistura's office said in a statement.
The group heads include Jan Egeland, a former top UN official and current chair of the Norwegian Refugee Council who will lead the safety and protection group, as well as Nicolas Michel, a Swiss national and former UN legal counsel, in charge of the group on political and legal affairs.
Also named was Volker Perthes, a German academic and Syria specialist who will focus on the military and counter-terrorism, with the fourth group headed by Sweden's Birgitta Holst Alani, who will lead the group on reconstructing the country.
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De Mistura said he hopes these groups can lay the groundwork before representatives of the various factions in Syria join the talks.
But Syrian President Bashar al-Assad's regime has reportedly warned him the outcomes of the working groups cannot be binding.
The conflict among Assad's forces and various rebel groups including Islamist extremists has killed nearly a quarter of a million people since 2011 and forced more than four million to flee the country. Millions more have been displaced within Syria.
Hundreds of thousands of Syrian refugees have reached Greece this year, fuelling Europe's migrant crisis and leading to growing calls for a political solution to end the fighting.
"This is the defining humanitarian challenge of our times," De Mistura said. "The Syrians deserve that we move faster towards a political solution".