I know almost nothing about the TV show Human Target: Siobhan watches it and sometimes I am in the room and hear a bit about it, but not much. I know even less about the comic book with which it shares a name, but which I have heard very little else. But one thing I did notice from the show, which apparently didn't get used much in the show, is a premise that I think would make a great roleplaying game. That was simply that the lead character didn't merely protect someone but actually stood in for them, pretending to be them long enough to both prevent the assassination and find out who was behind it long enough to stop it.
As a roleplaying game it has a number of nice features. First, there's a lot of variety of adventures that you can set up without any strain finding excuses for people to go on them: they get hired, and the number of reasons someone might contract a hit on someone else is legion, as are the number of ways that the story can backtrack from the victim to the perpetrators, the reason, and the ways it can be resolved.
Second, it encourages you to have a group which automatically gets to share spotlight time. You need males and females, party members of different ages and races, enough so that any given client can have someone in the group that can look like them (with the help of costuming and disguise). Everyone has to get a chance to be in the "point man" role because everyone's going to be the one who looks closest to the next client. Also means everyone has to have enough combat chops to take that position, but there's also tons of room for further specialization (disguise expert, demolitions, detective, etc.), so no one ever ends up being left out when the scene gets to the inevitable action and combat scenes.
Those scenes would have great reasons to have not just gunfights but also hand-to-hand (since the "target" would often have to be unarmed) along with concealed weapons and most of the clichés of the action genre.
Plus it lends itself very well to an episodic structure. You wouldn't have a lot of "arc" -- you'd have mostly individual adventures, making it easy to pick up and run with it, even after long periods of downtime. You could certainly have recurring "villains" in the form of a group of assassins that periodically are hired to hit the people that our heroes end up protecting -- you could even have one of their members be a particularly slippery and cocky hitman who crosses horns with the characters regularly, with a final resolution of the conflict never coming up -- they could even have a sort of "gentleman's rivalry" relationship. But while that'd get you a lot of the fun of a longer story it wouldn't tie you down to one.
About the only problem with it: if someone is hiring someone to kill you, how many ways can the bodyguards contrive not only to protect you for now, but to eliminate the threat indefinitely? I can think of a bunch of them. (Keep them alive long enough to give their deposition, or for the paperwork to clear. Figure out why the hit was arranged and then find out who really is responsible. Find the drug lord who set it up and finally get them caught up with by the law. Etc.) But it might be a strain to keep finding reasons why the hit wouldn't just keep having another hitman ordered once the last one didn't make it.