The invention provides peptides, variants of peptides, peptide fragments, and peptidomimetics that can inhibit the protease activity of tumor necrosis factor alpha converting enzyme. The invention also provides coupled proteins containing a partner protein coupled to a peptide, peptide fragment, or peptidomimetic. The invention also provides polyproteins containing at least two peptides, peptide fragments, or coupled proteins that are connected through a linker. Isolated nucleic acid segments, expression cassettes, and nucleic acid constructs are also provided by the invention. The invention also provides antibodies and aptamers. Pharmaceutical compositions are provided by the invention. Methods to lower or increase levels of active tumor necrosis factor alpha in a mammal are also provided.