In Geneva, Secretary of State John Kerry was once more locked in talks with Russian counterpart Sergei Lavrov but US officials warned talks could not go on forever without a breakthrough.
The two powers back opposite sides in the five-year conflict, with Moscow supporting the regime of President Bashar al-Assad and the US behind a coalition of rebel groups it regards as moderate.
Senior officials travelling with Kerry said he would not have flown out once again to new face-to-face talks with Lavrov unless he thought there was a chance of progress.
But they warned there was no guarantee of a final agreement within the narrow window before both men return home later Friday, coming just four days after the pair met in China and failed to narrow their differences.
The ministers met in the familiar confines of a hotel on the shore of Lake Geneva and made brief remarks to reporters about North Korea's latest nuclear test before beginning closed-door talks on Syria.
UN envoy on Syria, Staffan de Mistura, said a successful outcome from the talks could provide a major boost towards resolving the conflict that has killed 290,000 people.
"(It) would have a major impact on humanitarian access, and in turn would have a positive impact on the way the political process would be relaunched," de Mistura said in Geneva.
'Back to square one'
Washington wants concrete steps from Russia to force Assad to stop bombing his own people, respect a ceasefire and lift the siege of Aleppo.
"We need to see a situation where it's clear within whatever is being agreed with the Russians that there won't be a siege of Aleppo," a senior US official told reporters.
Pro-regime forces have taken back a strategically important district on Aleppo's southern outskirts, rolling back nearly every gain from a major month-long rebel offensive there, the Syrian Observatory for Human Rights said Thursday.
The government advance further seals off Aleppo's opposition-held eastern districts and regime troops backed by the Russian air force have completely encircled opposition-held neighbourhoods.
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Meanwhile, the top military commander of the Army of Conquest, the largest rebel alliance, was killed in an air strike during a meeting of the leaders of the anti-government group, Islamist sources said Thursday.
The former Al-Nusra Front, an Al-Qaeda affiliate recently renamed Fateh al-Sham Front, announced "the martyrdom" of commander Abu Omar Sarakeb on Twitter, in the biggest blow to the group since its formation early last year.
"Rebels are now back to square one, under an even more ruthless siege," Rami Abdel Rahman, head of the observatory, told AFP.
Shops in the east of Aleppo have been struggling since Sunday to secure goods and prices are skyrocketing.
"The price of a kilo of meat rose from 3,000 pounds to 6,000 (from $6 to $12)," complained father-of-three Ahmad in the strike-hit district of Bustan al-Qasr.
Ahead of the Geneva talks, the US pressed Russia for a "true cessation of hostilities" against a backdrop of continued military turmoil but warned that its patience is running thin.
US Defence Secretary Ash Carter told BBC radio on Thursday there was "quite a long way to go" before a final peace deal could be struck.
State Department spokesman John Kirby said the talks would "focus on reducing violence, expanding humanitarian assistance for the Syrian people, and moving toward a political solution needed to end the civil war."
In exchange, US officials said, Russia will enjoy closer military cooperation with the US forces fighting the Islamic State group and former Nusra Front, jihadist groups not party to the ceasefire.
Adding to the flurry of diplomatic efforts, Turkish President Recep Tayyip Erdogan and Russian counterpart Vladimir Putin also agreed to intensify efforts for a ceasefire "as soon as possible" in Aleppo, the Turkish news agency Anadolu reported.
Lavrov has suggested that problems in another part of the world -- namely, US sanctions against Russia over the Ukraine crisis -- may be hampering efforts between the former Cold War rivals to resolve the Syrian crisis.
The Syrian war -- which began as a pro-democracy revolt in 2011 but morphed into a multi-front conflict after the regime unleashed a crackdown -- has killed more than 290,000 people and forced more than half the population to flee their homes.
IS has used the chaos to spread throughout the country and into Iraq.