The ABC drama - a loose spinoff from Whedon's movie blockbuster The Avengers - will feature original characters not present in the Marvel films franchise.
One of the new leads will be Skye, a "fun, smart" and "confident" woman in her late 20s, "with an ability to get the upper hand by using her wit and charm", TVLine has reported.
Other characters include the physically capable but socially awkward Agent Grant Ward and the "hardcore", "damaged" weapons expert Agent Althea Rice.
Technical whiz Agent Leo Fitz and scientific genius Agent Jemma Simmons will also feature as regular characters, with the pair said to share "a sibling relationship".
Joss Whedon is expected to direct the S.H.I.E.L.D. pilot and will also work on the show's writing team alongside his brother Jed (Spartacus) and Maurissa Tancharoen (Drop Dead Diva).
Actress Lizzy Caplan - who appeared in Marvel's short film Item 47 - recently ruled out a role on the series, citing her commitment to forthcoming Showtime drama Masters of Sex.
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Watch an alternative opening scene for The Avengers below: