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It is claimed that St. Paul spent two years here, in the crypt under the church, whilst under house arrest waiting for his trial. This conflicts with the tradition regarding San Paolo alla Regola. The same was also claimed for St Peter, Paul's secretary Luke, Peter's disciple Martial, St John.
The first Christian place of worship here was a 5th-century oratory (chapel with welfare centre) in the Roman building beneath the present church. This was constructed within the remains of a large Roman warehouse, some 250 metres (820 ft) long, which has also been excavated. The church's upper level was added in the 9th century, and murals added to the lower level between the 7th and 9th centuries (these have been detached for conservation reasons). The cosmatesque pavement from this phase survives.
The church's 13th century icon of the Virgin Advocate, said to have performed many miracles, and relics of the 3rd century Deacon and martyr Agapitus lie beneath it. The Arcus Novus (an arch erected by emperor Diocletian in 303-304), which stood on this site were destroyed during reconstruction of the church in the late 15th century, c. 1491. Antonio Tebaldeo, poet and friend of Raphael, was buried at the end of the north aisle in 1537, though his tomb was designed in 1776.
The church was renovated in 1639 by Cosimo Fanzago, but the facade, with its Corinthian columns imposing vertical emphasis, was completed (1658-1660) based on a design by Pietro da Cortona. He appears to evoke a triumphal arch in the facade. The high altar Madonna Advocata (1636) is one of the few paintings in churches attributed to Bernini (perhaps by Santi Ghetti). The ciborium in the apse is made of alabaster and lapis-lazuli. The first excavations of the site also occurred at this date, as commemorated by a relief in the crypt by Cosimo Fancelli. The families of Joseph and Lucien Bonaparte were buried here in the 19th century.
Along the right side of the nave, the first altarpiece is a Martydom of St Andrew (1685) by Giacinto Brandi, while the second altarpiece is a Saints Giuseppe, Nicola, and Biagio by Giuseppe Ghezzi. In the chapel to the left of the apse, is a Madonna with child and Saints Cyriac and Catherine by Giovanni Odazzi. The second altar on the left has a Saint Paul baptizes Sabine and children by Pier Leone Ghezzi while the first altarpiece is a Virgin and Saints Lawrence and Anthony by Pietro de Pietri. Six oval paintings on the right nave include canvases by P. de Pietri and Agostino Masucci. On the left nave are five ovals, painted by P. de Pietri, Masucci, and Giovanni Domenico Piastrini.
An altar in the lower church has a marble bas relief by Cosimo Fancelli.
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