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  • Review Article
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Blocking NO synthesis: how, where and why?

Nature Reviews Drug Discovery volume 1, pages 939–950 (2002)Cite this article

Key Points

  • Nitric oxide (NO) is an intracellular and intercellular messenger molecule that has been implicated in a wide range of physiological processes.

  • Overproduction of NO can cause tissue damage and dysregulated cellular signalling, and seems to be a key feature of pathogenesis in several inflammatory and degenerative disorders.

  • Three isoforms of nitric oxide synthase (NOS) have been identified: endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). Although all three have important physiological roles, it is overproduction of NO from iNOS and nNOS that is important in certain disease states. These isoforms are therefore potential targets for new treatments. NO donation or boosting NO effects is also a target for treatments, but this article focuses solely on inhibition.

  • Studies with pharmacological inhibitors of NOS isozymes, and NOS-isoform knockout mice, indicate that blockade of individual NOS isozymes might produce therapeutic benefit, but will also be associated with harmful effects. For long-term treatment, a drug must not inhibit eNOS, as this would cause atherosclerosis and have significant adverse cardiovascular effects.

  • The active site of NOS isozymes is significantly conserved, so that isoform selectivity has not been easy to achieve. Nonetheless, compounds are now available that show specificity for inhibition of iNOS or nNOS over eNOS. Furthermore, compounds have been identified that inhibit activity through inhibition of dimerization or inhibition of cofactor binding. Compounds that block NO generation have therapeutic potential, and some are close to entering clinical trials. Potential targets include asthma, arthritis, neurodegenerative disorders, cancer, gastrointestinal inflammation and pain.

  • Even isoform-selective inhibition of NOS is likely to be associated with significant unwanted side effects. Partial inhibition of NOS isozymes might be a better option than complete or near complete inhibition. Even then, it seems that the role of NO might change from harmful to helpful during the course of a single process. For example, iNOS activity can be involved in tissue destruction, and in wound repair and resolution of inflammation.

  • Alternative approaches to decreasing harmful generation of NO while leaving physiological NO unaffected include inhibition of enzymes that regulate cofactors for NOS, manipulation of substrate levels or inhibition of enzymes that metabolize endogenous inhibitors of NOS.

  • Drugs that affect the activity of specific NOS isoforms are soon to enter clinical trials. Earlier experimental studies in humans with isoform non-selective inhibitors indicate that major biological effects can be expected, and not all of them will be beneficial. Nonetheless, the potential for therapeutic benefit makes it important that such drugs enter trials and are evaluated in clinical disease.

Abstract

Nitric oxide (NO) is a key physiological mediator, and the association of disordered NO generation with many pathological conditions has led to much interest in pharmacologically modulating NO levels. However, the wide range of processes in which NO has been implicated, and the fact that increases or decreases in NO levels might be therapeutically desirable depending on the condition or even at different stages of the same condition, pose considerable challenges for drug development. Here, we focus on the rationale and potential for approaches that reduce NO synthesis, which have led to the development of several compounds that will shortly be entering clinical trials.

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Figure 1: The NOS pathway.
Figure 2: Loss of eNOS causes vascular disease.
Figure 3: Effects of L-NMMA in a patient with severe septic shock.
Figure 4: Inhibitors of NOS.
Figure 5: The DDAH/NOS pathway.

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Acknowledgements

Work in the laboratory of P. V. is generously supported by grants from the British Heart Foundation, the Wellcome Trust and the Medical Research Council. The authors are grateful to R. Knowles, N. Boughton-Smith, and C. S. Raman for information provided, and to A. Hobbs for critical reading of the manuscript. Figure 3 was prepared by S. Rossiter. From the work of the authors, University College London (UCL) holds patents in relation to DDAH as a target for drug action.

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Authors and Affiliations

  1. Department of Medicine, Centre for Clinical Pharmacology, British Heart Foundation (BHF) Laboratories, University College London, 5 University Street, London, WC1E 6JJ, UK

    Patrick Vallance & James Leiper

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  1. Patrick Vallance
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Correspondence to Patrick Vallance.

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DATABASES

LocusLink

aconitase

ApoE

arginase

arginine deiminases

arginine glycine amidinotransferase

argininosuccinate synthase

calmodulin

caveolin-1

DDAH

diamine oxidase

dystrophin

eNOS

eNos

iNOS

iNos

nNOS

nNos

PIN

soluble guanylyl cyclase

thioredoxin

TP53

VEGF

OMIM

Alzheimer's disease

Celiac disease

multiple sclerosis

Parkinson's disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

nitric oxide: role in human disease

nitric oxide: synthesis and action

Protein Data Bank

Glossary

APOPTOSIS

Programmed cell death.

CASPASES

A family of intracellular cysteine proteases that are responsible for apoptosis.

PRODRUG

A pharmacologically inactive compound that is converted to the active form of the drug by endogenous enzymes or metabolism. It is generally designed to overcome problems associated with stability, toxicity, lack of specificity or limited (oral) bioavailability.

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Vallance, P., Leiper, J. Blocking NO synthesis: how, where and why?. Nat Rev Drug Discov 1, 939–950 (2002). https://doi.org/10.1038/nrd960

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