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