Amphiphilic desmuramyl peptides for the rational design of new vaccine adjuvants: Synthesis, in vitro modulation of inflammatory response and molecular docking studies

Khan, Farooq-Ahmad; Nasim, Nourina; Wang, Yan; Alhazmi, Alaa; Sanam, Mehar; Ul-Haq, Zaheer; Damayanthi, Y.; Ulanova, Marina; Jiang, Zi‐Hua

doi:10.1016/j.ejmech.2020.112863

Cited by 10 publications

(7 citation statements)

References 69 publications

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“…209 Recently, many bioactive molecules have been reported to deal with inflammatory markers. 210,211 Thirumurugan et al synthesized indole-bearing pyridine derivatives and evaluated their anti-inflammatory activity against rat-paw edema. All compounds had remarkable anti-inflammatory activity, particularly 67-68, which demonstrated significantly higher activity than the standard drug indomethacin (Figure 37).…”

Section: Anti-inflammatory Drugs and Active Compoundsmentioning

confidence: 99%

The Expanding Role of Pyridine and Dihydropyridine Scaffolds in Drug Design

Ling

Hao

Liang

et al. 2021

DDDT

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220

114

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Pyridine-based ring systems are one of the most extensively used heterocycles in the field of drug design, primarily due to their profound effect on pharmacological activity, which has led to the discovery of numerous broad-spectrum therapeutic agents. In the US FDA database, there are 95 approved pharmaceuticals that stem from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), abiraterone acetate (prostate cancer), tacrine (Alzheimer's), ciclopirox (ringworm and athlete's foot), crizotinib (cancer), nifedipine (Raynaud's syndrome and premature birth), piroxicam (NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), and many more. Their remarkable therapeutic applications have encouraged researchers to prepare a larger number of biologically active compounds decorated with pyridine or dihydropyridine, expandeing the scope of finding a cure for other ailments. It is thus anticipated that myriad new pharmaceuticals containing the two heterocycles will be available in the forthcoming decade. This review examines the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the most recent developments from 2010 to date, highlighting the ever-expanding role of both scaffolds in the field of medicinal chemistry and drug development.

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Section: Anti-inflammatory Drugs and Active Compoundsmentioning

confidence: 99%

The Expanding Role of Pyridine and Dihydropyridine Scaffolds in Drug Design

Ling

Hao

Liang

et al. 2021

DDDT

Self Cite

220

114

View full text Add to dashboard Cite

show abstract

“…[14] Recently, we also explored DMPs for the rational design of new vaccine adjuvants, wherein lipophilic chain of moderate length is thought to play a major role in their immunomodulatory properties. [34] In order to design potent innate immune modulators against viral infections, structure-activity relationship data of MDP and its mimics were analyzed, which clearly showed the inevitability of the LÀ D configuration in the dipeptide (Ala-isoGln) moiety. In this pharmacophoric unit, the L-alanine can be substituted with an amino acid of similar nature, such as L-valine or L-serine, but the D-isoglutamine cannot be exchanged.…”

Section: Introductionmentioning

confidence: 99%

Improved Synthesis of D‐Isoglutamine: Rapid Access to Desmuramyl Analogues of Muramyl Dipeptide for the Activation of Intracellular NOD2 Receptor and Vaccine Adjuvant Applications

Khan

Khanam

et al. 2021

Eur J Org Chem

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Muramyl dipeptide (MDP) -the smallest immunomodulatory unit of bacterial peptidoglycan -has adjuvant activity and triggers the innate immune system against bacterial and viral infections. The inherited drawbacks of MDP, such as pyrogenicity and poor macrophage penetration, can be resolved by structural modifications, thereby improving its pharmacological profile and adjuvant activity. Herein, several desmuramyl analogues of MDP were designed by replacing the carbohydrate fragment (MurNAc) of the parent molecule with an immunomodulatory xanthine scaffold. The LÀ D configurations of the pharmacophoric dipeptidyl moiety were conserved and alkyl chains of moderate length were introduced at isoglutamine to enhance their cellular uptake. The synthesis of these analogues features a novel synthetic route for D-isoglutamine fragment with an overall yield of > 50 % in ten to eleven steps. This sufficiently flexible approach provides rapid access to desmuramyl analogues of MDP on a gram scale, which can help accelerate the development of novel NOD2 agonists and immunoadjuvants.

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“…The software has already proven highly successful for a range of applications. [ 16 , 17 , 18 , 19 , 20 , 21 ] With the combination of wet experiments including a variety of mutants and substrates we were able to understand this unique and unprecedented behavior regarding the enantioselectivity of these enzymes. Furthermore, based on this rational insight into the stereochemical properties of such enzymes, we were capable to calculate mutants with superior and dramatically increased enantioselectivities.…”

Section: Introductionmentioning

confidence: 99%

Rationalizing the Unprecedented Stereochemistry of an Enzymatic Nitrile Synthesis through a Combined Computational and Experimental Approach

2021

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In this contribution, the unique and unprecedented stereochemical phenomenon of an aldoxime dehydratase‐catalyzed enantioselective dehydration of racemic E‐ and Z‐aldoximes with selective formation of both enantiomeric forms of a chiral nitrile is rationalized by means of molecular modelling, comprising in silico mutations and docking studies. This theoretical investigation gave detailed insight into why with the same enzyme the use of racemic E‐ and Z‐aldoximes leads to opposite forms of the chiral nitrile. The calculated mutants with a larger or smaller cavity in the active site were then prepared and used in biotransformations, showing the theoretically predicted decrease and increase of the enantioselectivities in these nitrile syntheses. This validated model also enabled the rational design of mutants with a smaller cavity, which gave superior enantioselectivities compared to the known wild‐type enzyme, with excellent E‐values of up to E>200 when the mutant OxdRE‐Leu145Phe was utilized.

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Amphiphilic desmuramyl peptides for the rational design of new vaccine adjuvants: Synthesis, in vitro modulation of inflammatory response and molecular docking studies

Cited by 10 publications

References 69 publications

The Expanding Role of Pyridine and Dihydropyridine Scaffolds in Drug Design

The Expanding Role of Pyridine and Dihydropyridine Scaffolds in Drug Design

Improved Synthesis of D‐Isoglutamine: Rapid Access to Desmuramyl Analogues of Muramyl Dipeptide for the Activation of Intracellular NOD2 Receptor and Vaccine Adjuvant Applications

Rationalizing the Unprecedented Stereochemistry of an Enzymatic Nitrile Synthesis through a Combined Computational and Experimental Approach

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