Gingipain inhibitors as an innovative therapy for periodontal and associated-systemic diseases: a systematic review

Abstract Periodontal diseases (PDs) are prevalent chronic inflammatory conditions linked to the progression of systemic disorders. Gingipains, cysteine proteases produced by Porphyromonas gingivalis , are key virulence factors involved in PD pathogenesis and host-tissue degradation. Inhibiting these enzymes has emerged as a promising therapeutic approach. Objective This systematic review evaluates the potential of gingipain inhibitors in the management of PDs and related systemic conditions. Methods A systematic search was conducted across PubMed, Scopus, and Web of Science using the PICOS framework. Studies were evaluated based on their objectives, experimental models, inhibitor types, and outcomes. Results Seven preclinical studies met the inclusion criteria. No clinical studies were identified. In preclinical models, gingipain inhibitors demonstrated consistent therapeutic benefits, including reduced inflammation, bacterial load, and tissue destruction in PDs, as well as improved outcomes in cardiovascular and AD models. Dual inhibitors targeting both Rgp and Kgp enzymes were more effective than single-target agents. Conclusion Gingipain inhibitors hold promise as therapeutic agents for PDs and associated systemic diseases. However, the absence of clinical studies highlights the need for further development and clinical evaluation to support their translational potential. Clinical relevance By targeting specific and key components of host–bacterium interactions, gingipain inhibitors represent a promising adjunctive therapy for modulating periopathogen virulence factors, thereby mitigating the progression of PDs and associated systemic diseases.