Trinidad Montero-Melendez trained as a Pharmacologist and obtained her PhD in Biochemistry and Molecular Biology at the University of Granada, Spain. She later joined the William Harvey Institute under the supervision of Professor Mauro Perretti, to work on understanding the pro-resolving potential of melanocortin receptors. During that period, she discovered the pro-resolving activities of the molecule AP1189 and its novel biased mode of action, which entered clinical development shortly after. She has also contributed to the pre-clinical development of several other melanocortin drug candidates for the treatment of inflammatory conditions and has participated in large high-throughput drug screening programmes for the identification of novel pro-resolving drugs. Another contribution to science includes the discovery of a novel mechanism of induction of senescence in synovial fibroblasts with therapeutic potential in diseases like rheumatoid arthritis.
Trini has published over 30 peer-reviewed publications as well as articles for the general public and children in the magazines The Biochemist and Frontiers for Young Minds.
Memberships and Awards:
Member of ICSA -International Cellular Senescence Association.
QMUL Life Sciences Initiative Seed Award, 2019
Queen Mary Innovation “Post-Doc Innovator Award”, 2017
WHRI - Outstanding Young Investigator Award, WHNYC 2015
Senescence and melanocortins
The melanocortin system is comprised by five receptors (MC1-5) and the endogenous peptides ACTH, a-,b-, and g-MSH. Over the last >10 years, we have advanced the field by discovering the pro-resolving actions of melanocortin agonists and by contributing to the pre-clinical development of several compounds in collaboration with industry, which are now undergoing clinical development. More recently, we discovered a new action of selective MC1 agonists which is the induction of cellular senescence in aberrantly activated fibroblasts, favouring the resolution of inflammation in models of arthritis. We are currently investigating the detailed mode of action of this novel mechanism and exploring other conditions for therapeutic application to scale up the translational impact of this discovery.
The melanocortin receptor MC1 is encoded by a highly polymorphic gene for which more than 900 genetic variants (SNPs) have been identified. MC1 is highly expressed in melanocytes, the skin cells responsible for the production of melanin. Many of these variants cause a loss-of-function on the receptor leading to reduced production of melanin. MC1 gene variation is responsible for the diversity in human normal pigmentation, reflected in skin and hair colour, and it is strongly associated with red hair. MC1 is mainly responsible for the tanning response upon UV stimulation and it is strongly associated with skin cancer risk. However, the high frequency of these variants in the population may impact on the development of MC1- based therapies. We are investigating what is the impact of carrying a variant on MC1R gene on the anti-inflammatory properties of melanocortin drugs.
Drug discovery - Resolution Pharmacology
Current medicines for the clinical management of inflammatory diseases act by inhibiting specific enzymes or antagonising specific receptors or blocking their ligands. In the past decade, a new paradigm in our understanding of the inflammatory process has emerged with the appreciation of genetic, molecular, and cellular mechanisms that are engaged to actively resolve inflammation. Mediators of resolution share fundamental properties to terminate the inflammatory reaction and organise the ‘cleaning phase’ within the affected tissue, as required for the regain of homeostasis and return to normal physiological function. Targeting of those mediators of resolution is what we termed “Resolution Pharmacology”. In this line, we are working on the discovery and development of novel compounds targeting the melanocortin and the formyl peptide receptor systems. In addition, we actively collaborate with the pharmaceutical industry to progress in the development of drug candidates targeting the resolution of inflammation.
Full list of publications here
- Montero-Melendez T, Nagano A, Chelala C, Filer A, Buckley CD, Perretti M. Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis. Nature Communications 2020,11(1):745.
- Patruno S, Garrido-Mesa J, Romano M, Perretti M, Montero-Melendez T. Ligand bias and its association with pro-resolving actions of melanocortin drugs. Frontiers in Pharmacology 2018, 9:919. doi: 10.3389/fphar.2018.00919
- Montero-Melendez T, Forfar RA, Cook JM, Jerman JC, Taylor DL, Perretti M. Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3. Cellular and Molecular Life Sciences 2017,74(7):1335-1345.
- Perretti M, Leroy X, Bland EJ, Montero-Melendez T. Resolution Pharmacology: Opportunities for Therapeutic Innovation in Inflammation. Trends in Pharmacological Sciences. 2015 Aug 21. pii: S0165-6147(15)00157-1.
- Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D'Acquisto F, Bland EJ, Bombardieri M, Pitzalis C, Perretti M, Marelli-Berg FM, Mauro C. Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions. PLoS Biology. 2015 Jul 16;13(7):e1002202.
- Montero-Melendez T. ACTH: The Forgotten Therapy. Seminars in Immunology. 2015;27(3):216-26.
- Montero-Melendez T, Gobbetti T, Cooray SN, Jonassen TEN, Perretti M. Biased agonism as a novel strategy to harness the pro-resolving properties of melanocortin receptors without eliciting melanogenic effects. The Journal of Immunology. 2015;194(7):3381-8.
- Montero-Melendez T, Fernandes Moreira Madeira M, Norling LN, Alsam A, Curtis MA, da Silva TA, Perretti M. Association between periodontal disease and inflammatory arthritis reveals modulatory functions by melanocortin receptor type 3. American Journal of Pathology 2014;184(8):2333-41.
- Montero-Melendez T, Perretti M. Connections in Pharmacology: innovation serving translational medicine. Drug Discovery Today 2014;19(7):820-3.
- Dalli J, Norling LV, Montero-Melendez T, Canova DF, Lashin H, Pavlov AM, Sukhorukov GB, Hinds CH, Perretti M. Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis. EMBO Molecular Medicine 2014;6(1):27-42
- Cooray SN, Gobbetti T, Montero-Melendez T, McArthur S, Thompson D, Clark AJL, Flower RJ, Perretti M. Ligand-specific activation of ALX/FPR2: identification of conformational changes associated with pro-resolving functional responses. PNAS 2013;110(45):18232-7.
- Dalli J*, Montero-Melendez T* ,Norling LV, Yin X, Hinds C, Haskard D, Mayr M, Perretti M. Heterogeneity in neutrophil microparticles reveals distinct proteome and functional properties. Molecular and Cellular Proteomics 2013, 12(8):2205-2219 (*share first authorship)
- Montero-Melendez T, Dalli J, Parretti M. Gene expression signature based approach identifies a pro-resolving mechanism of action for histone deacetylase inhibitors. Cell Death and Differentiation 2013;20(4):567-575.
- Vessillier S, Adams G, Montero-Melendez T, Jones R, Seed M, Perretti M, Chernajovsky Y. Molecular engineering of short half-life small peptides (VIP, αMSH and γ₃MSH) fused to latency-associated peptide results in improved anti-inflammatory therapeutics. Annals of Rheumatic Diseases. 2012 Jan;71(1):143-9.
- Montero-Melendez T, H.B. Patel, M. Seed, S. Nielsen, T. Jonassen, M. Perretti. The melanocortin agonist AP214 exerts anti-inflammatory and pro-resolving properties: evidence for a major involvement of the melanocortin receptor type 3. American Journal of Pathology 2011, 179(1):259-269.
- Montero-Melendez T, H.B. Patel, M. Perretti. Role of melanocortin receptors in the regulation of gouty inflammation. Current Rheumatology Reports, 2011;13(2):138-45.
Science communication to the general public:
- Montero-Melendez T . May inflammation be with you! Frontiers for Young Minds 2018, 6:51. doi: 10.3389/frym.2018.00051
- Perretti M, Montero-Melendez T. Resolution in an ‘over-inflamed era’. The Biochemist 2017, 39(4):4-7.
External: Prof Christopher D Buckley (University of Birmingham; Kennedy Institute of Rheumatology), Dr Andrew Filer (University of Birmingham), Prof Thomas Jonassen (University of Copenhagen; WHRI- International Scientific Advisory Board), Prof David Abraham (UCL)