Can the 747 be re-engined as a twin? Since more and more airlines are dropping the 747 for the 777 or equivalent due to fuel efficiency, a theoretical question came to mind.

What do you think is preventing Boeing from creating a 747 twinjet (two engines instead of 4).

I know there are probably design/engineering issues associated with such a conversion, but I reckon that if it was done it may increase sales to go up against the A380? Not sure the math as well, but perhaps the engine from the 777 could be used or configured for higher thrust?
Currently, the 777 has engines that have a max thrust of 115,000 lbf, for a total of 230,000 lbf of thrust. The 747-8 has engines with a max thrust of 66,500 lbf, each, for a total of 266000. And just to throw in for comparison, the A380, currently has engines each producing 72,000 lbf of thrust, and a total of 288,000 lbf.

Right now the 777 has some of the highest thrust producing engines in commercial service. This does not take into account the extra thrust that is required for engine out issues. With a 2 engine design you have to have enough extra thrust for loss of engine during take-off at max take off weight. Whereas with a 4 engine design, you only have to have enough thrust to account for loss of 1 engine. So for a 747 twin engine aircraft, as a rough estimate you'd need to have each engine produce at least 150,000 lbf of thrust if not more.