C1-INH EcN Construct Question¶

C1-INH could exploit upstream complement initiation by inhibiting C1r, C1s, and MASP proteases, but an exact EcN-produced material must first be shown to attain its native serpin function and retain that function under the intended exposure conditions. COMP-037 does not answer that question.

The COMP-037 tombstone is non-runnable. Its pLDDT-as-accessibility mapping, sequence-filter scores, risk colors, cleavage and survival claims, glycosylation-feasibility verdict, construct preference, EcN assignment, and cross-payload conclusions are invalid. Git retains the historical implementation; no numerical proxy output is current evidence.

What remains source-backed:

UniProt P05155 annotates the C1-INH reactive region and two intrachain disulfides. These are sequence features, not evidence that an EcN product folds, survives, or inhibits its targets.
Native C1-INH is glycosylated (In Vitro; PMID 9799502 and PMID 29381136). Those records do not establish whether a particular unglycosylated bacterial product retains useful function.
Productive target engagement and unproductive cleavage at or near a serpin reactive-center loop are distinct kinetic outcomes (Mechanistic Extrapolation; source: the P05155 annotation and established serpin mechanism). Their competition has not been measured for an EcN-produced C1-INH configuration.

Research conjecture — productive inhibition may outcompete cleavage in an exact EcN configuration

Grounded premises: C1-INH uses a reactive-center serpin mechanism and is natively glycosylated (In Vitro / Mechanistic Extrapolation; sources: UniProt P05155, PMID 9799502, and PMID 29381136). Exact EcN-produced C1-INH materials have not been shown here to attain native fold or retained C1r, C1s, and MASP inhibition.

Novel leap: An exact EcN-produced C1-INH configuration may retain enough native serpin function for productive target engagement to outcompete unproductive cleavage under the intended exposure. No direct evidence establishes this for an EcN-produced C1-INH configuration.

Why it matters: A positive configuration-level result would preserve an upstream-complement payload without declaring EcN, C1-INH, or a multi-payload architecture generally viable.

Discriminating observation: For each prespecified construct × export route × folding-support configuration, measure product identity, intact recovery, native fold or validated structural-function readout, disulfide state, concentration-dependent inhibition of C1r/C1s/MASP-2, matched protease-challenge cleavage, and retained inhibition after challenge. Advance only the exact configuration that passes prespecified quality and kinetic gates.

A negative result kills only the tested construct × route × support × exposure condition. It does not reject upstream complement inhibition or another production chassis. Access, delivery, safety, and portfolio ranking remain separate questions.