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Table 1 A summarize of natural product-derived PD-1/PD-L1 inhibitors

From: Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

Natural products Methodology Key finding(s)
Name Type Sub-type
Amphotericin B Macrocyclic Macrolide AlphaLISA; MD Not active
Bacitracin Cyclic peptide
Everolimus Macrolide
Clarithromycin Macrolide
Cyclosporin A Cyclic peptide
Actinomycin D Cyclic peptide Weak PD1/PD-L1 inhibitor (less than 20% inhibition at 50 µM)
Cynocobalamin Porphyrin
Bryostatin Macrolide
Candicidin Macrolide
Geldanamycin Polyketide
Ivermectin B1a Macrolide
Macbecin Ansamycin
Metocurine Alkaloid
Monocrotaline Alkaloid
Nystatin Macrolide
Plerixafor Bicyclam
Sirolimus Macrolide
Troleandomycin Macrolide
Rifampin Ansamycin PD1/PD-L1 inhibition was 47.9% at 50 µM
Rifabutin PD1/PD-L1 inhibition was 66.7% at 50 µM
IC50 was 25 µM
Rifapentine PD1/PD-L1 inhibition was 52.1% at 50 µM
Rifamycin SV PD1/PD-L1 inhibition was 34.5% at 50 µM
Formyl rifamycin PD1/PD-L1 inhibition was 40.2% at 50 µM
Rifaximin PD1/PD-L1 inhibition was 24.0% at 50 µM
Gramicidin S Macrocyclic Cyclic peptide HTRF; NMR; SPR; CD; MD PD1/PD-L1 inhibition was 6.86% at 20 µM
Gramicidin S derivative PD1/PD-L1 inhibition was 95.8% at 20 µM; IC50 was 1.42 µM
Conserved the β-sheet conformation of the gramicidin S skeleton
KD was 1.66 mM and 5.67 µM for PD-1 and PD-L1, respectively
Kaempferol Phenolic Flavonoid ELISA; BLI; SPR
Cell based assay
MD
IC50 for blocking PD-1/PD-L1 was 7.797 µM
Cellular PD-1/PD-L1inhibition IC50 was 14.46 µM
Calculated binding energy was -5.4 and -5.0 kcal/mol for PD-1 and PD-L1, respectively
Kaempferol-7-O-rhamnoside Flavonoid Cellular PD-1/PD-L1inhibition IC50 was 14.46 µM
KD was 31.1 and 19.7 µM for PD-1 and PD-L1, respectively
Calculated binding energy was -5.6 and -5.3 kcal/mol for PD-1 and PD-L1, respectively
Cosmosiin Phenolic Flavonoid ELISA; BLI
Cell based assay
MD
Increased T-cell functional activity by 1.91-fold; Had KD value of 386 and 85 µM for PD-1 and PD-L1, respectively
Fit to a 1:1 binding model to PD-1 and PD-L1; Had a predicted binding affinity of − 6.2 and − 5.8 kcal/mol for PD-1 and PD-L1, respectively
Apigenin Flavonoid Increased T-cell functional activity by 2.03-fold
Eriodictyol Phenolic Flavanone ELISA Had an IC50 of 0.04 µM for PD-1/PD-L1
Fisetin Flavonol Had an IC50 of 0.04 µM for PD-1/PD-L1
Glyasperin C Phenolic Isoflavan HTRF Had an PD-1/PD-L1 inhibition rate of 64.3% at 100 µM
Caffeoylquinic acid Phenolic SPR KD = 1.24 × 10−5 M for PD-1; not detected for PD-L1
3-O-caffeoylquinic acid Caffeoylquinic acid KD = 1.95 × 10−6 M for PD-1; 1.71 × 10−5 M for PD-L1
4-O-caffeoylquinic acid Caffeoylquinic acid KD = 5.07 × 10−6 M for PD-1; not detected for PD-L1
5-O-caffeoylquinic acid Caffeoylquinic acid KD = 1.68 × 10−5 M for PD-1; 8.13 × 10−5 M for PD-L1
Ellagic acid Phenolic ELISA
WB
Cell based assay
Blocked PD-1/PD-L1 binding with an IC50 value of 22.92 μg/mL
Bound to PD-1 and PD-L1 in WB;
ZINC 67,902,090 Heterocyclic Pyrrolidine-oxadiazole AlphaLISA
WB
MD
PD-1/PD-L1 inhibition potency was 30% as compared to BMS-202
ZINC 12,529,904 PD-1/PD-L1 inhibition potency was 40% as compared to BMS-202