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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